The c.68_69del variant in BRCA1 is a deletion of two nucleotides, predicted to encode a frameshift with consequent premature termination of the protein at codon 17 of the frameshift, or amino acid 39 (p.Glu23ValfsTer17). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA1, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA1 exon 3 (PM5_Strong (PTC)). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 32546644) (PS3 met). In summary, this variant meets the criteria to be classified as a Pathogenic variant variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PS3).
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.68_69del (p.Glu23fs)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007294.4(BRCA1):c.68_69del (p.Glu23fs)
Variation ID: 17662 Accession: VCV000017662.149
- Type and length
-
Microsatellite, 2 bp
- Location
-
Cytogenetic: 17q21.31 17: 43124028-43124029 (GRCh38) [ NCBI UCSC ] 17: 41276045-41276046 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 12, 2013 Oct 20, 2024 Jun 11, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- E23fs
- Other names
-
NP_009225.1:p.Glu23ValfsTer17
NM_007294.4(BRCA1):c.68_69del
187delAG
185delAG
- Canonical SPDI
- NC_000017.11:43124027:CTCT:CT
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
loss_of_function_variant; Sequence Ontology [ SO:0002054]
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13041 | 14847 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (32) |
criteria provided, multiple submitters, no conflicts
|
May 27, 2024 | RCV000019230.61 | |
| risk factor (1) |
no assertion criteria provided
|
Oct 1, 2008 | RCV000019231.12 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 2, 2024 | RCV000056295.21 | |
| Pathogenic (14) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV000034761.51 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 13, 2023 | RCV000131394.24 | |
| Pathogenic (15) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000213650.66 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Mar 4, 2022 | RCV000735481.13 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 1, 2018 | RCV000785197.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001353942.9 | |
|
Invasive medullary breast carcinoma
|
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001836711.9 |
| Pathogenic (1) |
criteria provided, single submitter
|
May 4, 2022 | RCV002496414.8 | |
| Pathogenic (1) |
no assertion criteria provided
|
Feb 21, 2023 | RCV003128128.8 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 11, 2023 | RCV003225925.8 | |
| Pathogenic (1) |
reviewed by expert panel
|
Jun 11, 2024 | RCV004566751.1 | |
|
BRCA1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Feb 16, 2024 | RCV004554604.3 |
| click to load more click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 11, 2024)
|
reviewed by expert panel
Method: curation
|
BRCA1-related cancer predisposition
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV004101425.2 First in ClinVar: Nov 11, 2023 Last updated: Jun 17, 2024 |
Comment:
The c.68_69del variant in BRCA1 is a deletion of two nucleotides, predicted to encode a frameshift with consequent premature termination of the protein at codon … (more)
The c.68_69del variant in BRCA1 is a deletion of two nucleotides, predicted to encode a frameshift with consequent premature termination of the protein at codon 17 of the frameshift, or amino acid 39 (p.Glu23ValfsTer17). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA1, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA1 exon 3 (PM5_Strong (PTC)). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 32546644) (PS3 met). In summary, this variant meets the criteria to be classified as a Pathogenic variant variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PS3). (less)
|
|
|
Pathogenic
(Nov 20, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes, no
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266036.1
First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
pancreatic cancer (present)
Age: 60-69 years
Observation 2:
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Nov 03, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Michigan Medical Genetics Laboratories, University of Michigan
Accession: SCV000195875.1
First in ClinVar: May 06, 2016 Last updated: May 06, 2016 |
Tissue: Blood
|
|
|
Pathogenic
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary Breast and Ovarian Cancer
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000403078.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The c.68_69delAG (p.Glu23ValfsTer17) variant, also commonly known as 185delAG, is a frameshift variant that is very well described in the literature as one of the … (more)
The c.68_69delAG (p.Glu23ValfsTer17) variant, also commonly known as 185delAG, is a frameshift variant that is very well described in the literature as one of the most frequent variants found in breast cancer (Shattuck-Eidens et al. 1995; Offit et al. 1996). It was first identified in a study by Simard et al. (1994) in index cases from four unrelated Canadian families with hereditary breast and ovarian cancer (HBOC). Wang et al. (2012) conducted a meta-analysis of over 29 studies published between 2000 and 2010 and determined the overall frequency of the p.Glu23ValfsTer17 variant in 2128 breast cancer cases to be 0.072. The variant is one of three known common founder germline variants primarily found in individuals of Ashkenazi Jewish heritage (Struewing et al. 1997; Abeliovich et al. 1997; Laitman et al. 2013) and has been detected in 20% of Ashkenazi Jewish women diagnosed with breast cancer before age 42 years (Offit et al 1996). In the Ashkenazi Jewish population, the variant is associated with a risk of between 56% and 83% of breast cancer and of between 14% and 58% risk of ovarian cancer by the age of 70 (Struewing et al. 1997; Antoniou et al. 2005; Finkelman et al. 2012). The variant has been observed in individuals of other ethnicities (Wang et al. 2012; Laitman et al. 2013). The variant is reported at a frequency of 0.00042 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Based on the available evidence, the p.Glu23ValfsTer17 variant is classified as pathogenic for hereditary breast and ovarian cancer. (less)
|
|
|
Pathogenic
(Feb 23, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000540943.1
First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jul 01, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Department of Medical Genetics, Oslo University Hospital
Accession: SCV000564332.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 13
|
|
|
Pathogenic
(Jan 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Genologica Medica
Additional submitter:
Servicio Andaluz de Salud, Hospital Universitario Virgen de la Victoria
Accession: SCV000577914.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Family history: yes
Ethnicity/Population group: Causasians
Geographic origin: Spain
Tissue: Blood
Secondary finding: no
|
|
|
Pathogenic
(Dec 02, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
{Breast-ovarian cancer, familial, 1}
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000593688.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
|
Pathogenic
(May 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000227400.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
|
|
|
Pathogenic
(Jan 22, 2019)
|
criteria provided, single submitter
Method: research
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI_GT
Accession: SCV000993552.1 First in ClinVar: Oct 01, 2019 Last updated: Oct 01, 2019 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary Breast Carcinoma
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000693502.3
First in ClinVar: Feb 24, 2015 Last updated: May 04, 2020 |
Comment:
This sequence change deletes 2 nucleotides from exon 2 of the BRCA1 mRNA (c.68_69delAG), causing a frameshift after codon 23 and the creation of a … (more)
This sequence change deletes 2 nucleotides from exon 2 of the BRCA1 mRNA (c.68_69delAG), causing a frameshift after codon 23 and the creation of a premature translation stop signal 17 amino acid residues later - p.(Glu23Valfs*17). This is expected to result in an absent or disrupted protein product.This variant, also known as BRCA1_185delAG or 187delAG, is one of three main pathogenic founder variants in the Ashkenazi Jewish population although it has been observed in individuals from other ethnicities as well (PMID: 23199084 ). This mutation has been described in the mutation database ClinVar(Variation ID: 17662). (less)
|
|
|
Pathogenic
(Jun 05, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449768.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 15
|
|
|
Pathogenic
(Apr 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499755.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
|
|
|
Pathogenic
(Sep 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271311.5
First in ClinVar: May 29, 2016 Last updated: May 29, 2021 |
Comment:
The p.Glu23ValfsX17 variant in BRCA1 has been reported in numerous individuals with hereditary breast and ovarian cancer (HBOC) and is a known pathogenic Ashkenazi Jewish … (more)
The p.Glu23ValfsX17 variant in BRCA1 has been reported in numerous individuals with hereditary breast and ovarian cancer (HBOC) and is a known pathogenic Ashkenazi Jewish founder variant (Struewing 1997 PMID: 9145676, Abeliovich 2013 PMID: 9042909). It has also been identified in 0.4% (42/10368) of Ashkenazi Jewish and 0.009% (11/128780) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that this frequency is low enough to be consistent with the frequency of HBOC in the general population. This frameshift variant is predicted to alter the protein's amino acid sequence beginning at position 23 and lead to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with HBOC. Additionally, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282348.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein and presence in multiple affected individuals. ACMG/AMP Criteria applied: PVS1, PS4_strong. (less)
Number of individuals with the variant: 19
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Molecular Endocrinology Laboratory, Christian Medical College
Accession: SCV002003976.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: no
Allele origin:
germline
|
GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited
Accession: SCV002097608.1
First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022 |
Sex: female
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Invasive medullary breast carcinoma
Affected status: yes
Allele origin:
germline
|
GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited
Accession: SCV002097613.1
First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022 |
Sex: female
|
|
|
Pathogenic
(Jun 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580991.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS4, PP1_MOD, PS3_SUP, PM2_SUP
|
Number of individuals with the variant: 3
Sex: female
|
|
|
Pathogenic
(Oct 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000326390.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
|
|
|
Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002525990.2
First in ClinVar: Jun 18, 2022 Last updated: Dec 24, 2022 |
Comment:
The BRCA1 c.68_69del (p.Glu23ValfsTer17) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or … (more)
The BRCA1 c.68_69del (p.Glu23ValfsTer17) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has a maximum subpopulation frequency of 0.41% in gnomAD v2.1.1, where it is primarily found in the Ashkenazi Jewish population (https://gnomad.broadinstitute.org/variant/17-41276044-ACT-A?dataset=gnomad_r2_1). This variant has been reported in multiple individuals with breast cancer and/or ovarian cancer (PMID: 14576434, 26718727, 21503673, 22430266, 23633455, 22752604), prostate (PMID: 22516946) and pancreatic cancer (PMID: 20711688, 24737347, 23658460, 26440929). It is a well-established pathogenic founder variant in the Ashkenazi Jewish population (PMID: 9042909, 22430266). This alteration is also known as 185delAG or 187delAG in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4. (less)
|
|
|
Pathogenic
(May 30, 2014)
|
criteria provided, single submitter
Method: literature only
|
Breast-ovarian cancer, familial 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220360.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Breast-ovarian cancer, familial, susceptibility to, 1 Pancreatic cancer, susceptibility to, 4 Fanconi anemia, complementation group S
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002814217.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Oct 16, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000278833.11
First in ClinVar: May 29, 2016 Last updated: Jun 10, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 185delAG or 187delAG; This variant is associated with the following publications: (PMID: 18594935, 26071757, 26221963, 27259235, 28049106, 26822237, 29176636, 31948886, 22703879, 22535016, 22516946, 22009639, 23633455, 23658460, 22763381, 23086583, 19906413, 21503673, 22430266, 20711688, 22752604, 22006311, 7611277, 23867111, 25556971, 24737347, 26440929, 26689913, 26641009, 27553291, 23788959, 26718727, 26681312, 27836010, 29321669, 27062684, 28528518, 11802208, 28477318, 29339979, 29752822, 28324225, 27989354, 29907814, 29431110, 29560538, 26556299, 10464624, 29470806, 28390335, 28993434, 26357657, 29161300, 30702160, 30067863, 30152102, 30630528, 30122538, 30186769, 30720243, 30322717, 30093976, 31159747, 30113427, 31372034, 30489631, 30612635, 31454914, 31528241, 29625052, 31447099, 31980526, 34308366, 33646313, 10739756, 10733239, 11597388, 9042909, 12220453, 31589614, 32341426, 9634504, 10885601, 32719484, 33556450, 12491828, 32338768, 30875412, 30787465, 16030426, 33224455) (less)
|
|
|
Pathogenic
(Mar 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296272.7
First in ClinVar: Jun 24, 2016 Last updated: Jan 06, 2024 |
Comment:
This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. The frequency of this … (more)
This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.0041 (42/10368 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported as one of the common pathogenic BRCA founder variants in the Ashkenazi Jewish population (PMIDs: 22430266 (2012), 14576434 (2003), 8841191 (1996), 7550349 (1995)). The variant has been reported in individuals from multiple populations with a personal or family history of breast and/or ovarian cancer (PMIDs: 35377489 (2022), 33758026 (2022), 35039532 (2022), 35264596 (2022), 35356428 (2022), 35710434 (2022), 33646313 (2021), 32341426 (2020), 31528241 (2019), 31372034 (2019), 31159747 (2019), 30875412 (2019), 30630528 (2019), 30489631 (2019)) and prostate cancer (PMIDs: 33556450 (2021), 32338768 (2020), 31948886 (2020)). Functional studies report the variant disrupts proper protein function (PMID: 35459234 (2022)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020211.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000077108.18
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu23Valfs*17) in the BRCA1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu23Valfs*17) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs386833395, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer, and pancreatic cancer (PMID: 9042909, 15994883, 22430266, 23658460, 24737347). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8571953, 8651293, 9042909, 9921907, 15994883, 22430266, 23658460, 24737347). This variant is also known as 185delAG or 187delAG. ClinVar contains an entry for this variant (Variation ID: 17662). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602669.6
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
The BRCA1 c.68_69delAG; p.Glu23ValfsTer17 variant (rs386833395), also known as 185delAG, is a well known founder variant associated with breast, ovarian, and pancreatic cancer in the … (more)
The BRCA1 c.68_69delAG; p.Glu23ValfsTer17 variant (rs386833395), also known as 185delAG, is a well known founder variant associated with breast, ovarian, and pancreatic cancer in the Ashkenazi Jewish population as well as other ethnic populations (Abeliovich 1997, Antoniou 2005, King 2003, Laitman 2019, Lucas 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 17662), and is found in the general population with an overall allele frequency of 0.02% (58/282442 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Glu23ValfsTer17 variant is considered to be pathogenic. [**Use the AJ BRCA template under BRCA NGS, OR Make sure to add the AJ recommendations from that template "If this individual is of Ashkenazi Jewish ancestry…"**] References: Abeliovich D et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet. 1997 Mar;60(3):505-14. Antoniou AC et al. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J Med Genet. 2005 Jul;42(7):602-3. King MC et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003 Oct 24;302(5645):643-6. Laitman Y et al. The spectrum of BRCA1 and BRCA2 pathogenic sequence variants in Middle Eastern, North African, and South European countries. Hum Mutat. 2019 Nov;40(11):e1-e23. Lucas AL et al. BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts. Cancer. 2014 Jul 1;120(13):1960-7. (less)
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Pathogenic
(Jan 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004823702.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This variant deletes 2 nucleotides in exon 2 of the BRCA1 gene, causing a frameshift and a premature translational stop signal. This variant is also … (more)
This variant deletes 2 nucleotides in exon 2 of the BRCA1 gene, causing a frameshift and a premature translational stop signal. This variant is also known as 185delAG and 187delAG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.96-1.14% minor allele frequency (PMID: 7550349, 8571953, 30152102). This variant has been reported in dozens of individuals and families affected with breast and ovarian cancer (PMID: 7894492, 7611277, 7837387, 8533757, 8531968, 8642955, 9042909, 9150153, 21643751, 30480775, 35020120). This variant also has been observed in individuals from diverse ethnicities in Africa, America, Asia and Europe (PMID: 8651293, 24312913). The risk of female breast cancer among carriers of this mutation is 55-83% by age 70, and the risk of ovarian cancer is 12-58% by age 70 (PMID: 9145676, 15994883, 22430266). A breast cancer case-control meta-analysis has detected this variant in 30/60436 cases and 8/53453 unaffected individuals with an odds ratio (OR) of 3.317 (95%CI 1.52 to 7.235) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001114). This variant has been identified in 58/282442 chromosomes (42/10368 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 57
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Pathogenic
(Apr 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: no
Allele origin:
maternal
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Genomic Medicine Lab, University of California San Francisco
Accession: SCV004847144.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
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Pathogenic
(Dec 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000778781.3
First in ClinVar: Jun 23, 2018 Last updated: Jun 02, 2024 |
Number of individuals with the variant: 19
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Pathogenic
(Mar 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004212668.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jul 14, 2017)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Bioinformatics dept., Datar Cancer Genetics Limited, India
Accession: SCV000583605.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Indication for testing: Clinical features observed in the individual
Age: 40-49 years
Sex: female
Ethnicity/Population group: South Asian
Geographic origin: India
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Pathogenic
(Apr 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000586860.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
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Pathogenic
(Apr 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Department of Pathology and Molecular Medicine, Queen's University
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000588022.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
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Pathogenic
(Aug 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699291.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The BRCA1 c.68_69delAG (p.Glu23Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense … (more)
Variant summary: The BRCA1 c.68_69delAG (p.Glu23Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest is one of the most common Jewish founder mutations. Multiple publications have cited the variant in affected individuals. This variant was found in 29/120972 control chromosomes at a frequency of 0.0002397, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Dec 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746289.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Geographic origin: Iran
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Pathogenic
(May 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV000803154.1
First in ClinVar: Oct 21, 2017 Last updated: Oct 21, 2017 |
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Pathogenic
(May 25, 2017)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839891.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The c.68_69del (p.Glu23Valfs*17) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 14576434, 26718727, 21503673, 22430266, 23633455, … (more)
The c.68_69del (p.Glu23Valfs*17) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 14576434, 26718727, 21503673, 22430266, 23633455, 22752604, referred as c.185delAG in some publications]. This variant is a founder mutation in Ashkenazi Jews with a frequency of about 1% [PMID 14576434]. The variant has also been detected in patients with prostate [PMID 22516946] and pancreatic cancer [PMID 20711688, 24737347, 23658460, 26440929]. This one bp deletion in exon 2 results in a frameshift and the creation of a premature stop codon. Functional in vitro assays showed that this variant was deleterious [PMID 23867111]. This variant has been reported in 31 individuals from the ExAC database (http://exac.broadinstitute.org/variant/22-29091226-TA-T). This variant is thus classified as pathogenic (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447639.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Breast carcinoma (present)
Sex: female
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Pathogenic
(Dec 15, 2020)
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criteria provided, single submitter
Method: research
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Familial cancer of breast
Affected status: no
Allele origin:
germline
|
Department of Pediatrics, Memorial Sloan Kettering Cancer Center
Accession: SCV001478110.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
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Pathogenic
(Mar 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002107151.2
First in ClinVar: Mar 28, 2022 Last updated: Apr 02, 2022 |
Comment:
The c.68_69del;p.(Glu23Valfs*17) is a null frameshift variant (NMD) in the BRCA1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a … (more)
The c.68_69del;p.(Glu23Valfs*17) is a null frameshift variant (NMD) in the BRCA1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17662; PMID: 7611277; PMID: 7894492; PMID: 14576434; PMID: 21503673; PMID: 22430266)PS4. The variant is present at low allele frequencies population databases (rs80357914 – gnomAD 0.001446%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
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Pathogenic
(Apr 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Accession: SCV002026049.2
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 3
Geographic origin: South Africa
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Pathogenic
(Oct 07, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002537890.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA1 c.68_69delAG (p.E23VfsX17) is a well characterized pathogenic variant that has been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (PMID: 9042909). … (more)
The BRCA1 c.68_69delAG (p.E23VfsX17) is a well characterized pathogenic variant that has been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (PMID: 9042909). This variant is also known as 185_186delAG, 187delAG or 185delAG in the literature. The c.68_69delAG variant is a founder variant in the Ashkenazi Jewish population (PMID: 9042909, 9150153). This variant deletes 2 nucleotides causing a frameshift at codon 23 which creates a premature stop codon at position 17 of the new reading frame. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). Loss of function variants in BRCA1 are known to be pathogenic (PMID: 29446198). This variant was observed in 42/10368 chromosomes of the Ashkenazi Jewish subpopulation, with no homozygotes, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID:32461654) and has been reported in ClinVar (Variation ID17662). Based on the current evidence available, this variant was interpreted as a pathogenic . (less)
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Pathogenic
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000839317.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Pathogenic
(Mar 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000901065.2 First in ClinVar: May 06, 2019 Last updated: Mar 11, 2023 |
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Pathogenic
(Aug 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Accession: SCV002764582.2
First in ClinVar: Dec 17, 2022 Last updated: May 20, 2023 |
Comment:
The c.68_69del variant in BRCA1 (also referred as c.185delAG) is an established pathogenic variant [ClinVar ID:17662] that is predicted (p.(Glu23fs)) to result in atruncated or … (more)
The c.68_69del variant in BRCA1 (also referred as c.185delAG) is an established pathogenic variant [ClinVar ID:17662] that is predicted (p.(Glu23fs)) to result in atruncated or absent BRCA1 protein due to nonsense mediated decay. The c.68_69del variant is a founder mutation in Ashkenazi Jewish population with a frequency of about 1% [PMID: 14576434]. The c.68_69del variant has been reported in multiple individuals with breast and/or ovarian, prostate, and pancreatic cancers [PMID:14576434, 20711688, 22516946, 23633455, 22752604]. Based on available evidence, this c.68_69del (p.(Glu23fs)) variant identified in BRCA1 is reported as Pathogenic. (less)
Observation 1:
Clinical Features:
Hyperlipidemia (present) , Diabetes mellitus (present)
Secondary finding: yes
Observation 2:
Clinical Features:
Hyperlipidemia (present) , Hepatic steatosis (present)
Secondary finding: yes
Observation 3:
Clinical Features:
Hyperlipidemia (present) , Hepatic steatosis (present) , Type 2 diabetes mellitus (present)
Secondary finding: yes
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Pathogenic
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009407.3
First in ClinVar: Oct 30, 2021 Last updated: Jul 16, 2023 |
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Pathogenic
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002551076.4
First in ClinVar: Jul 23, 2022 Last updated: Aug 18, 2023 |
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Pathogenic
(Mar 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000292122.5
First in ClinVar: Jul 08, 2016 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 2 nucleotides in exon 2 of the BRCA1 gene, causing a frameshift and a premature translational stop signal. This variant is also … (more)
This variant deletes 2 nucleotides in exon 2 of the BRCA1 gene, causing a frameshift and a premature translational stop signal. This variant is also known as 185delAG and 187delAG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.96-1.14% minor allele frequency (PMID: 7550349, 8571953, 30152102). This variant has been reported in dozens of individuals and families affected with breast and ovarian cancer (PMID: 7894492, 7611277, 7837387, 8533757, 8531968, 8642955, 9042909, 9150153, 21643751, 30480775, 35020120). This variant also has been observed in individuals from diverse ethnicities in Africa, America, Asia and Europe (PMID: 8651293, 24312913). The risk of female breast cancer among carriers of this mutation is 55-83% by age 70, and the risk of ovarian cancer is 12-58% by age 70 (PMID: 9145676, 15994883, 22430266). A breast cancer case-control meta-analysis has detected this variant in 30/60436 cases and 8/53453 unaffected individuals with an odds ratio (OR) of 3.317 (95%CI 1.52 to 7.235) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001114). This variant has been identified in 58/282442 chromosomes (42/10368 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jun 28, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186370.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.68_69delAG (p.E23Vfs*17) alteration, located in exon 2 (coding exon 1) of the BRCA1 gene, consists of a deletion of 2 nucleotides from position 68 … (more)
The c.68_69delAG (p.E23Vfs*17) alteration, located in exon 2 (coding exon 1) of the BRCA1 gene, consists of a deletion of 2 nucleotides from position 68 to 69, causing a translational frameshift with a predicted alternate stop codon after 17 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this variant has an overall frequency of 0.021% (58/282442) total alleles studied. The highest observed frequency was 0.405% (42/10368) of Ashkenazi Jewish alleles. This alteration is one of three well-characterized Ashkenazi Jewish founder mutations, with an overall carrier frequency of nearly 1% in this population (Struewing, 1995; Hartge, 1999). Average female breast cancer and ovarian cancer risks (by age 70) associated with this specific mutation have been estimated at 64% (range: 34-80%) and 14% (range: 2-24%), respectively (Antoniou, 2005). Additionally, this germline mutation has been reported in individuals of Ashkenazi Jewish descent with personal and/or family history of pancreatic cancer (Lucas, 2013; Lucas, 2014). It has also been identified in multiple Spanish hereditary breast and ovarian cancer families (Gabaldó Barrios, 2017). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(May 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Accession: SCV005045898.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
Comment:
PVS1; PM5_PTC_Strong
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Pathogenic
(Jul 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198273.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(May 20, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100646.2
First in ClinVar: Nov 04, 2023 Last updated: Oct 08, 2024 |
Comment:
The frameshift c.68_69del (p.Glu23ValfsTer17) variant in the BRCA1 gene has been reported in a heterozygous state in individuals affected with Hereditary Breast and Ovarian Cancer … (more)
The frameshift c.68_69del (p.Glu23ValfsTer17) variant in the BRCA1 gene has been reported in a heterozygous state in individuals affected with Hereditary Breast and Ovarian Cancer (Petrucelli N et al. 2022; Rajagopal T et al., 2022). Functional assays showed this variant was deleterious (Bouwman P et al. 2013). The p.Glu23ValfsTer17 variant has an allele frequency of 0.02% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). This variant causes a frameshift starting with codon Glutamic Acid 23, changes this amino acid to Valine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Glu23ValfsTer17. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Neoplasm (present)
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Pathogenic
(Apr 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV005368055.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PVS1,PS3,PS4_MOD,PM5_STR
Clinical Features:
Ovarian carcinoma (present)
Sex: female
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Pathogenic
(Jun 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004027730.3
First in ClinVar: Aug 26, 2023 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PVS1,PS4
Clinical Features:
Ovarian carcinoma (present)
Sex: female
|
|
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Pathogenic
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250428.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
BRCA1: PVS1, PM2, PS4:Moderate
Number of individuals with the variant: 12
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Pathogenic
(Jul 24, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: unknown
Allele origin:
germline
|
Pathway Genomics
Accession: SCV000189887.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
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risk factor
(Oct 01, 2008)
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no assertion criteria provided
Method: literature only
|
PANCREATIC CANCER, SUSCEPTIBILITY TO, 4
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000053475.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Breast-Ovarian Cancer Susceptibility Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer (604370) for germline mutations in the coding region of … (more)
Breast-Ovarian Cancer Susceptibility Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer (604370) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 2-bp (AG185) deletion in the normal sequence TTA GAG of codons 22-23 in exon 3. The AGAG presumably predisposed to the deletion. This mutation changes the reading frame of the mRNA and causes a premature termination codon at position 39. This mutation was detected in index cases from 4 families that were not known to be related and originated from different areas in Canada. In these 4 families there were a total of 12 cases of breast cancer and 11 cases of ovarian cancer. Struewing et al. (1995) pointed out that all 10 published families with the 185delAG mutation (also called 187delAG) were Ashkenazi Jewish (of Eastern European origin). They knew of an eleventh Ashkenazi breast/ovarian cancer family with the 185delAG mutation; furthermore, only 1 Ashkenazi Jewish family was known to have a BRCA1 mutation other than 185delAG. In addition, Ashkenazi families with the 185delAG mutation appeared to share a common haplotype. In a study of 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, they observed the 185delAG mutation in 0.9% (95% confidence limit, 0.4%-1.8%), and in 815 reference individuals not selected for ethnic origin, none had the mutation. Roa et al. (1996) found the 185delAG mutation in 1.09% of approximately 3,000 Ashkenazi Jewish individuals and found the 5382insC mutation (113705.0018) in 0.13%. BRCA2 analysis on 3,085 individuals from the same population showed a carrier frequency of 1.52% for the 6174delT mutation (600185.0009). The expanded population-based study confirmed that the BRCA1 185delAG mutation and the BRCA2 6174delT mutation constituted the 2 most frequent mutant alleles predisposing to hereditary breast cancer among Ashkenazim and suggested a relatively lower penetrance for the 6174delT mutation in BRCA2. Bar-Sade et al. (1997) examined 639 unrelated healthy Jews of Iraqi extraction, a presumed low-risk group for the 185delAG mutation which occurs predominantly in Ashkenazim. Three individuals were identified as 185delAG mutation carriers, and haplotype analysis of the Iraqi mutation carriers showed that 2 of the Iraqis shared a haplotype in common with 6 Ashkenazi mutation carriers, and a third had a haplotype that differed by a single marker. This suggested to Bar-Sade et al. (1997) that the BRCA1 185delAG mutation may have arisen before the dispersion of the Jewish people in the Diaspora, at least at the time of Christ. Bar-Sade et al. (1998) extended their analyses to other non-Ashkenazi subsets: 354 of Moroccan origin, 200 Yemenites, and 150 Iranian Jews. Four of Moroccan origin (1.1%) and none of the Yemenites or Iranians were carriers of the 185delAG mutation. BRCA1 allelic patterns (haplotypes) were determined for 4 of these individuals and for 12 additional non-Ashkenazi 185delAG mutation carriers who had breast/ovarian cancer. The common 'Ashkenazi haplotype' was shared by 6 non-Ashkenazi individuals; 4 had a closely related pattern, and the rest (n = 6) displayed a distinct BRCA1 allelic pattern. The authors concluded that the 185delAG BRCA1 mutation occurs in some non-Ashkenazi populations at rates comparable with that of Ashkenazim. The majority of Jewish 185delAG mutation carriers have the same haplotype, supporting the founder effect notion, but dating the mutation's origin to an earlier date than previously estimated. The different allelic pattern at the BRCA1 locus in some Jewish mutation carriers might suggest that the mutation arose independently. Bandera et al. (1998) demonstrated the 185delAG mutation in 2 women with a personal or family history of breast cancer and papillary serous carcinoma of the peritoneum (PSCP). PSCP is histologically indistinguishable from serous epithelial ovarian carcinoma and it may develop years after oophorectomy. Schorge et al. (1998) demonstrated that the tumors were multifocal in these cases, indicating that patients with germline BRCA1 mutations may develop PSCP in addition to breast and ovarian carcinomas. Ah Mew et al. (2002) reported the 185delAG mutation in a non-Jewish Chilean family with no reported Jewish ancestry. The linked haplotype present in this family was identical to that identified in the Ashkenazi Jewish population. Buisson et al. (2006) found that BRCA1 transcripts bearing the 185delAG mutation are not degraded by nonsense-mediated mRNA decay. Using Western blot analysis, they examined HeLa cells transfected with minigenes for this transcript and another with a premature termination codon at position 36 and found that translation from these transcripts was reinitiated at codon 128. Pancreatic Cancer Susceptibility Al-Sukhni et al. (2008) found loss of heterozygosity at the BRCA1 locus in pancreatic tumor DNA from 5 (71%) of 7 patients with pancreatic cancer (PNCA4; 614320) who carried a heterozygous germline BRCA1 mutation. Three patients carried the 185delAG mutation. In contrast, only 1 (11%) of 9 patients with sporadic pancreatic cancer and no germline BRCA1 mutations showed LOH at the BRCA1 locus. Al-Sukhni et al. (2008) concluded that BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and suggested that individuals with these mutations be considered for pancreatic cancer-screening programs. (less)
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Pathogenic
(Oct 01, 2008)
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no assertion criteria provided
Method: literature only
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BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039518.4
First in ClinVar: Apr 04, 2013 Last updated: Apr 09, 2018 |
Comment on evidence:
Breast-Ovarian Cancer Susceptibility Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer (604370) for germline mutations in the coding region of … (more)
Breast-Ovarian Cancer Susceptibility Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer (604370) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 2-bp (AG185) deletion in the normal sequence TTA GAG of codons 22-23 in exon 3. The AGAG presumably predisposed to the deletion. This mutation changes the reading frame of the mRNA and causes a premature termination codon at position 39. This mutation was detected in index cases from 4 families that were not known to be related and originated from different areas in Canada. In these 4 families there were a total of 12 cases of breast cancer and 11 cases of ovarian cancer. Struewing et al. (1995) pointed out that all 10 published families with the 185delAG mutation (also called 187delAG) were Ashkenazi Jewish (of Eastern European origin). They knew of an eleventh Ashkenazi breast/ovarian cancer family with the 185delAG mutation; furthermore, only 1 Ashkenazi Jewish family was known to have a BRCA1 mutation other than 185delAG. In addition, Ashkenazi families with the 185delAG mutation appeared to share a common haplotype. In a study of 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, they observed the 185delAG mutation in 0.9% (95% confidence limit, 0.4%-1.8%), and in 815 reference individuals not selected for ethnic origin, none had the mutation. Roa et al. (1996) found the 185delAG mutation in 1.09% of approximately 3,000 Ashkenazi Jewish individuals and found the 5382insC mutation (113705.0018) in 0.13%. BRCA2 analysis on 3,085 individuals from the same population showed a carrier frequency of 1.52% for the 6174delT mutation (600185.0009). The expanded population-based study confirmed that the BRCA1 185delAG mutation and the BRCA2 6174delT mutation constituted the 2 most frequent mutant alleles predisposing to hereditary breast cancer among Ashkenazim and suggested a relatively lower penetrance for the 6174delT mutation in BRCA2. Bar-Sade et al. (1997) examined 639 unrelated healthy Jews of Iraqi extraction, a presumed low-risk group for the 185delAG mutation which occurs predominantly in Ashkenazim. Three individuals were identified as 185delAG mutation carriers, and haplotype analysis of the Iraqi mutation carriers showed that 2 of the Iraqis shared a haplotype in common with 6 Ashkenazi mutation carriers, and a third had a haplotype that differed by a single marker. This suggested to Bar-Sade et al. (1997) that the BRCA1 185delAG mutation may have arisen before the dispersion of the Jewish people in the Diaspora, at least at the time of Christ. Bar-Sade et al. (1998) extended their analyses to other non-Ashkenazi subsets: 354 of Moroccan origin, 200 Yemenites, and 150 Iranian Jews. Four of Moroccan origin (1.1%) and none of the Yemenites or Iranians were carriers of the 185delAG mutation. BRCA1 allelic patterns (haplotypes) were determined for 4 of these individuals and for 12 additional non-Ashkenazi 185delAG mutation carriers who had breast/ovarian cancer. The common 'Ashkenazi haplotype' was shared by 6 non-Ashkenazi individuals; 4 had a closely related pattern, and the rest (n = 6) displayed a distinct BRCA1 allelic pattern. The authors concluded that the 185delAG BRCA1 mutation occurs in some non-Ashkenazi populations at rates comparable with that of Ashkenazim. The majority of Jewish 185delAG mutation carriers have the same haplotype, supporting the founder effect notion, but dating the mutation's origin to an earlier date than previously estimated. The different allelic pattern at the BRCA1 locus in some Jewish mutation carriers might suggest that the mutation arose independently. Bandera et al. (1998) demonstrated the 185delAG mutation in 2 women with a personal or family history of breast cancer and papillary serous carcinoma of the peritoneum (PSCP). PSCP is histologically indistinguishable from serous epithelial ovarian carcinoma and it may develop years after oophorectomy. Schorge et al. (1998) demonstrated that the tumors were multifocal in these cases, indicating that patients with germline BRCA1 mutations may develop PSCP in addition to breast and ovarian carcinomas. Ah Mew et al. (2002) reported the 185delAG mutation in a non-Jewish Chilean family with no reported Jewish ancestry. The linked haplotype present in this family was identical to that identified in the Ashkenazi Jewish population. Buisson et al. (2006) found that BRCA1 transcripts bearing the 185delAG mutation are not degraded by nonsense-mediated mRNA decay. Using Western blot analysis, they examined HeLa cells transfected with minigenes for this transcript and another with a premature termination codon at position 36 and found that translation from these transcripts was reinitiated at codon 128. Pancreatic Cancer Susceptibility Al-Sukhni et al. (2008) found loss of heterozygosity at the BRCA1 locus in pancreatic tumor DNA from 5 (71%) of 7 patients with pancreatic cancer (PNCA4; 614320) who carried a heterozygous germline BRCA1 mutation. Three patients carried the 185delAG mutation. In contrast, only 1 (11%) of 9 patients with sporadic pancreatic cancer and no germline BRCA1 mutations showed LOH at the BRCA1 locus. Al-Sukhni et al. (2008) concluded that BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and suggested that individuals with these mutations be considered for pancreatic cancer-screening programs. (less)
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Pathogenic
(Jun 22, 2016)
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no assertion criteria provided
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000863618.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018 |
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Pathogenic
(Dec 01, 2018)
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no assertion criteria provided
Method: research
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Ovarian neoplasm
Affected status: yes
Allele origin:
germline
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German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000923765.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001905815.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965465.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Breast and ovarian cancer
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002032172.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
Age: 30-39 years
Sex: female
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037545.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
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Pathogenic
(Aug 26, 2022)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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BRCAlab, Lund University
Accession: SCV002589061.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
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Pathogenic
(Mar 11, 2023)
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no assertion criteria provided
Method: clinical testing
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Triple-negative breast cancer
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Cancer Genomics Lab, PINUM Cancer Hospital
Accession: SCV003914825.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Clinical Features:
Multifocal breast carcinoma (present)
Age: 40-49 years
Ethnicity/Population group: Punjabi
Geographic origin: Punjab
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Pathogenic
(May 05, 2023)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV003927207.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
This sequence change deletes 2 nucleotides from exon 2 of the BRCA1 mRNA (c.68_69delAG), causing a frameshift after codon 23 and the creation of a … (more)
This sequence change deletes 2 nucleotides from exon 2 of the BRCA1 mRNA (c.68_69delAG), causing a frameshift after codon 23 and the creation of a premature translation stop signal 17 amino acid residues later – p.Glu23Valfs*17). This is expected to result in an absent or disrupted protein product. This variant, also known as BRCA1_185delAG or 187delAG, is one of three main pathogenic founder variants in the Ashkenazi Jewish population although it has been observed in individuals from other ethnicities as well (PMID: 23199084 ). This mutation has been described in the mutation database ClinVar(Variation ID: 17662). Therefore, this variant has been classified as pathogenic. (less)
Sex: female
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Pathogenic
(May 24, 2021)
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no assertion criteria provided
Method: case-control
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)
Accession: SCV005061273.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
Secondary finding: no
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Pathogenic
(Feb 16, 2024)
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no assertion criteria provided
Method: clinical testing
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BRCA1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000806982.4
First in ClinVar: Jun 23, 2018 Last updated: Oct 08, 2024 |
Comment:
The BRCA1 c.68_69delAG variant is predicted to result in a frameshift and premature protein termination (p.Glu23Valfs*17). This variant, also described as 185delAG or 187delAG in … (more)
The BRCA1 c.68_69delAG variant is predicted to result in a frameshift and premature protein termination (p.Glu23Valfs*17). This variant, also described as 185delAG or 187delAG in the literature, has been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC) (OMIM #604370). This is a recurrent variant among individuals of Spanish origin and is a founder variant in the Ashkenazi Jewish population, identified in about 1% of Ashkenazi Jewish individuals unselected for breast cancer (Gabaldó Barrios et al. 2017. PubMed ID: 28477318; Finkelman et al. 2012. PubMed ID: 22430266; Struewing et al. 1997. PubMed ID:9145676; Roa et al. 1996. PubMed ID:8841191). This variant is frequently observed in the Ashkenazi Jewish population in gnomad. This variant is also found in individuals of diverse ancestry at variable frequencies. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/17662/). In summary, this variant is interpreted as pathogenic. (less)
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pathogenic
(Jul 13, 2012)
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no assertion criteria provided
Method: research
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Breast-ovarian cancer, familial
Affected status: no
Allele origin:
germline
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043189.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Pathogenic.
Number of individuals with the variant: 1
Age: 60-69 years
Sex: male
Ethnicity/Population group: Ashkenazi Jewish
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
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Pathogenic
(May 29, 2002)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline,
unknown
|
Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000144169.2
First in ClinVar: Apr 01, 2014 Last updated: Oct 11, 2015 |
Observation 1:
Number of individuals with the variant: 599
Observation 2:
Number of individuals with the variant: 32
Geographic origin: Ashkenazi
Observation 3:
Number of individuals with the variant: 1
Geographic origin: Ashkenazi, Central Eastern European
Observation 4:
Number of individuals with the variant: 1
Geographic origin: Ashkenazi, Central/Eastern European
Observation 5:
Number of individuals with the variant: 2
Geographic origin: Austria
Observation 6:
Number of individuals with the variant: 1
Geographic origin: Central/Eastern European
Observation 7:
Number of individuals with the variant: 7
Geographic origin: Netherlands
Observation 8:
Number of individuals with the variant: 1
Geographic origin: France
Observation 9:
Number of individuals with the variant: 1
Geographic origin: Hispanic
Observation 10:
Number of individuals with the variant: 1
Geographic origin: Mexican American
Observation 11:
Number of individuals with the variant: 1
Geographic origin: Native American
Observation 12:
Number of individuals with the variant: 1
Geographic origin: Western European, Ashkenazi
Observation 13:
Number of individuals with the variant: 1
Ethnicity/Population group: African
Observation 14:
Number of individuals with the variant: 1
Ethnicity/Population group: African, Latin American, Caribbean
Observation 15:
Number of individuals with the variant: 1075
Ethnicity/Population group: Ashkenazi
Observation 16:
Number of individuals with the variant: 3
Ethnicity/Population group: Ashkenazi
Geographic origin: France
Observation 17:
Number of individuals with the variant: 6
Ethnicity/Population group: Ashkenazi Jewish
Observation 18:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi Jewish
Geographic origin: American
Observation 19:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi Jewish
Geographic origin: Canada
Observation 20:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi Jewish
Geographic origin: Germany
Observation 21:
Number of individuals with the variant: 31
Ethnicity/Population group: Ashkenazi, Central/Eastern European
Observation 22:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi, Central/Eastern European, Nea
Observation 23:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi, Dutch, Italian
Observation 24:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi, Englishraine
Observation 25:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi, Greek
Observation 26:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi, Scandinavian
Observation 27:
Number of individuals with the variant: 2
Ethnicity/Population group: Ashkenazi, Sephardic
Observation 28:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi, Sephardic Jewish
Observation 29:
Number of individuals with the variant: 5
Ethnicity/Population group: Ashkenazi, Western European
Observation 30:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi, Western, Central/Eastern European
Observation 31:
Number of individuals with the variant: 2
Ethnicity/Population group: Asian
Observation 32:
Number of individuals with the variant: 1
Ethnicity/Population group: Asian, Ashkenazi, Western European
Observation 33:
Number of individuals with the variant: 2
Ethnicity/Population group: Asian, Indian
Observation 34:
Number of individuals with the variant: 1
Ethnicity/Population group: Austrian, Jewish, Polish
Observation 35:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Observation 36:
Number of individuals with the variant: 6
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Observation 37:
Number of individuals with the variant: 6
Ethnicity/Population group: Caucasian
Geographic origin: Netherlands
Observation 38:
Number of individuals with the variant: 5
Ethnicity/Population group: Caucasian
Geographic origin: English
Observation 39:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Italy
Observation 40:
Number of individuals with the variant: 6
Ethnicity/Population group: Caucasian
Geographic origin: Spain
Observation 41:
Number of individuals with the variant: 7
Ethnicity/Population group: Caucasian Non Hispanic
Observation 42:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian, Non Ashkenazi
Observation 43:
Number of individuals with the variant: 17
Ethnicity/Population group: Central/Eastern European
Observation 44:
Number of individuals with the variant: 1
Ethnicity/Population group: Central/Eastern European, Russian
Observation 45:
Number of individuals with the variant: 1
Ethnicity/Population group: Central/Eastern European, Russian, Polish
Observation 46:
Number of individuals with the variant: 1
Ethnicity/Population group: Central/Eastern European, Turkish, Greek
Observation 47:
Number of individuals with the variant: 1
Ethnicity/Population group: Chilean
Observation 48:
Number of individuals with the variant: 1
Ethnicity/Population group: English
Observation 49:
Number of individuals with the variant: 1
Ethnicity/Population group: English, Jewish
Observation 50:
Number of individuals with the variant: 1
Ethnicity/Population group: Englishraine German
Observation 51:
Number of individuals with the variant: 2
Ethnicity/Population group: Gypsy
Geographic origin: Spain
Observation 52:
Number of individuals with the variant: 3
Ethnicity/Population group: Indian
Geographic origin: Malaysia
Observation 53:
Number of individuals with the variant: 1
Ethnicity/Population group: Irish, German, Scottish, English, Welsh
Observation 54:
Number of individuals with the variant: 54
Ethnicity/Population group: Jewish
Observation 55:
Number of individuals with the variant: 1
Ethnicity/Population group: Jewish
Geographic origin: Chile
Observation 56:
Number of individuals with the variant: 1
Ethnicity/Population group: Jewish
Geographic origin: Germany
Observation 57:
Number of individuals with the variant: 1
Ethnicity/Population group: Jewish
Geographic origin: Norway
Observation 58:
Number of individuals with the variant: 1
Ethnicity/Population group: Jewish, Mixed
Observation 59:
Number of individuals with the variant: 21
Ethnicity/Population group: Latin American, Caribbean
Observation 60:
Number of individuals with the variant: 1
Ethnicity/Population group: Latin American, Caribbean, New Mexican
Observation 61:
Number of individuals with the variant: 1
Ethnicity/Population group: Latvian
Geographic origin: Latvia
Observation 62:
Number of individuals with the variant: 1
Ethnicity/Population group: Mediterranean
Observation 63:
Number of individuals with the variant: 2
Ethnicity/Population group: Mid, Near East
Observation 64:
Number of individuals with the variant: 6
Ethnicity/Population group: Native American
Observation 65:
Number of individuals with the variant: 1
Ethnicity/Population group: Native American, Western European
Observation 66:
Number of individuals with the variant: 5
Ethnicity/Population group: Near Eastern
Observation 67:
Number of individuals with the variant: 1
Ethnicity/Population group: Near Eastern, Sephardic Jewish
Observation 68:
Number of individuals with the variant: 1
Ethnicity/Population group: Patient Not Ashkenazi Jewish
Observation 69:
Number of individuals with the variant: 1
Ethnicity/Population group: Romanian, Ashkenazi Jewish
Observation 70:
Number of individuals with the variant: 1
Ethnicity/Population group: Romanian, Jewish
Observation 71:
Number of individuals with the variant: 1
Ethnicity/Population group: Russian Jewish
Observation 72:
Number of individuals with the variant: 1
Ethnicity/Population group: Russian, Ashkenazi Jewish
Observation 73:
Number of individuals with the variant: 1
Ethnicity/Population group: Russian, Polish
Observation 74:
Number of individuals with the variant: 2
Ethnicity/Population group: Spanish
Observation 75:
Number of individuals with the variant: 87
Ethnicity/Population group: Western European
Observation 76:
Number of individuals with the variant: 23
Ethnicity/Population group: Western European, Ashkenazi
Observation 77:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Ashkenazi, Central, Eas
Observation 78:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Ashkenazi, Central/Eastern European, Polish, Austrian
Observation 79:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Ashkenazi, English, Dutch
Observation 80:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Central/Eastern European
Observation 81:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Danish, German, Neth
Observation 82:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, French
Observation 83:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, French Canadian
Observation 84:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, French, English, Irish
Observation 85:
Number of individuals with the variant: 2
Ethnicity/Population group: Western European, French, Italian
Observation 86:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, French, Spanish
Observation 87:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Jewish
Observation 88:
Number of individuals with the variant: 2
Ethnicity/Population group: Western European, Latin American, Caribbe
Observation 89:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Native American, Centr
Observation 90:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Native American, Latin
Observation 91:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Near Eastern Mid Eastern
Observation 92:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Spanish Mexican
Observation 93:
Number of individuals with the variant: 1
Ethnicity/Population group: Western Europeanan, Central/Eastern European
Observation 94:
Number of individuals with the variant: 6
Ethnicity/Population group: Ashkenazi
Geographic origin: American
Observation 95:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: American
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Pathogenic
(Nov 14, 2013)
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no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
|
Sharing Clinical Reports Project (SCRP)
Accession: SCV000053880.6
First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2016 |
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Pathogenic
(Jan 31, 2014)
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no assertion criteria provided
Method: research
|
Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587006.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733684.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(Jun 11, 2019)
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no assertion criteria provided
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: yes
Allele origin:
germline
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CZECANCA consortium
Accession: SCV001451786.1
First in ClinVar: Dec 26, 2020 Last updated: Dec 26, 2020 |
Number of individuals with the variant: 6
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000591232.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The p.Glu23ValfsX17 deletion variant is one of three known founder pathogenic mutations common to individuals of Ashkenazi Jewish descent (Petrucelli 1998). This deletion is predicted … (more)
The p.Glu23ValfsX17 deletion variant is one of three known founder pathogenic mutations common to individuals of Ashkenazi Jewish descent (Petrucelli 1998). This deletion is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 23 and leads to a premature stop codon 17 codons downstream. This alteration is then predicted to lead to a truncated or absent protein product and loss of function. Loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. (less)
Number of individuals with the variant: 28
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Pathogenic
(Feb 21, 2023)
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no assertion criteria provided
Method: clinical testing
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Endometrial carcinoma
Affected status: yes
Allele origin:
germline
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CZECANCA consortium
Accession: SCV003804349.1
First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023 |
Number of individuals with the variant: 1
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
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not provided
(-)
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no classification provided
Method: literature only
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000086950.3
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
Comment:
Founder variant in Ashkenazi Jews; accounts for 72% of pathogenic variants in this population
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not provided
(-)
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no classification provided
Method: phenotyping only
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002074718.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment:
Variant interpreted as Pathogenic and reported on 12-11-2018 by Lab or GTR ID 505849. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 12-11-2018 by Lab or GTR ID 505849. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Family history (present)
Indication for testing: Diagnostic
Age: 40-49 years
Sex: male
Testing laboratory: Color Health, Inc
Date variant was reported to submitter: 2018-12-11
Testing laboratory interpretation: Pathogenic
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not provided
(-)
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no classification provided
Method: phenotyping only
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749327.2
First in ClinVar: Jul 18, 2021 Last updated: Jan 26, 2024 |
Comment:
Variant reported in multiple GenomeConnect-Invitae Patient Insights Network participants by Lab Invitae. Variant interpreted as Pathogenic and reported, most recently, on 02-06-2021 and on 03-26-2018. … (more)
Variant reported in multiple GenomeConnect-Invitae Patient Insights Network participants by Lab Invitae. Variant interpreted as Pathogenic and reported, most recently, on 02-06-2021 and on 03-26-2018. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Observation 1:
Clinical Features:
Bladder neoplasm (present)
Indication for testing: Diagnostic
Age: 80 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2021-02-06
Testing laboratory interpretation: Pathogenic
Observation 2:
Clinical Features:
Family history of cancer (present)
Indication for testing: Diagnostic
Age: 60-69 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2018-03-26
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
The c.68_69delAG (p.Glu23ValfsTer17) variant, also commonly known as 185delAG, is a frameshift variant that is very well described in the literature as one of the most frequent variants found in breast cancer (Shattuck-Eidens et al. 1995; Offit et al. 1996). It was first identified in a study by Simard et al. (1994) in index cases from four unrelated Canadian families with hereditary breast and ovarian cancer (HBOC). Wang et al. (2012) conducted a meta-analysis of over 29 studies published between 2000 and 2010 and determined the overall frequency of the p.Glu23ValfsTer17 variant in 2128 breast cancer cases to be 0.072. The variant is one of three known common founder germline variants primarily found in individuals of Ashkenazi Jewish heritage (Struewing et al. 1997; Abeliovich et al. 1997; Laitman et al. 2013) and has been detected in 20% of Ashkenazi Jewish women diagnosed with breast cancer before age 42 years (Offit et al 1996). In the Ashkenazi Jewish population, the variant is associated with a risk of between 56% and 83% of breast cancer and of between 14% and 58% risk of ovarian cancer by the age of 70 (Struewing et al. 1997; Antoniou et al. 2005; Finkelman et al. 2012). The variant has been observed in individuals of other ethnicities (Wang et al. 2012; Laitman et al. 2013). The variant is reported at a frequency of 0.00042 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Based on the available evidence, the p.Glu23ValfsTer17 variant is classified as pathogenic for hereditary breast and ovarian cancer.
Comment:
This sequence change deletes 2 nucleotides from exon 2 of the BRCA1 mRNA (c.68_69delAG), causing a frameshift after codon 23 and the creation of a premature translation stop signal 17 amino acid residues later - p.(Glu23Valfs*17). This is expected to result in an absent or disrupted protein product.This variant, also known as BRCA1_185delAG or 187delAG, is one of three main pathogenic founder variants in the Ashkenazi Jewish population although it has been observed in individuals from other ethnicities as well (PMID: 23199084 ). This mutation has been described in the mutation database ClinVar(Variation ID: 17662).
Comment:
The p.Glu23ValfsX17 variant in BRCA1 has been reported in numerous individuals with hereditary breast and ovarian cancer (HBOC) and is a known pathogenic Ashkenazi Jewish founder variant (Struewing 1997 PMID: 9145676, Abeliovich 2013 PMID: 9042909). It has also been identified in 0.4% (42/10368) of Ashkenazi Jewish and 0.009% (11/128780) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that this frequency is low enough to be consistent with the frequency of HBOC in the general population. This frameshift variant is predicted to alter the protein's amino acid sequence beginning at position 23 and lead to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with HBOC. Additionally, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282348.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein and presence in multiple affected individuals. ACMG/AMP Criteria applied: PVS1, PS4_strong.
Comment:
The BRCA1 c.68_69del (p.Glu23ValfsTer17) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has a maximum subpopulation frequency of 0.41% in gnomAD v2.1.1, where it is primarily found in the Ashkenazi Jewish population (https://gnomad.broadinstitute.org/variant/17-41276044-ACT-A?dataset=gnomad_r2_1). This variant has been reported in multiple individuals with breast cancer and/or ovarian cancer (PMID: 14576434, 26718727, 21503673, 22430266, 23633455, 22752604), prostate (PMID: 22516946) and pancreatic cancer (PMID: 20711688, 24737347, 23658460, 26440929). It is a well-established pathogenic founder variant in the Ashkenazi Jewish population (PMID: 9042909, 22430266). This alteration is also known as 185delAG or 187delAG in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 185delAG or 187delAG; This variant is associated with the following publications: (PMID: 18594935, 26071757, 26221963, 27259235, 28049106, 26822237, 29176636, 31948886, 22703879, 22535016, 22516946, 22009639, 23633455, 23658460, 22763381, 23086583, 19906413, 21503673, 22430266, 20711688, 22752604, 22006311, 7611277, 23867111, 25556971, 24737347, 26440929, 26689913, 26641009, 27553291, 23788959, 26718727, 26681312, 27836010, 29321669, 27062684, 28528518, 11802208, 28477318, 29339979, 29752822, 28324225, 27989354, 29907814, 29431110, 29560538, 26556299, 10464624, 29470806, 28390335, 28993434, 26357657, 29161300, 30702160, 30067863, 30152102, 30630528, 30122538, 30186769, 30720243, 30322717, 30093976, 31159747, 30113427, 31372034, 30489631, 30612635, 31454914, 31528241, 29625052, 31447099, 31980526, 34308366, 33646313, 10739756, 10733239, 11597388, 9042909, 12220453, 31589614, 32341426, 9634504, 10885601, 32719484, 33556450, 12491828, 32338768, 30875412, 30787465, 16030426, 33224455)
Comment:
This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.0041 (42/10368 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported as one of the common pathogenic BRCA founder variants in the Ashkenazi Jewish population (PMIDs: 22430266 (2012), 14576434 (2003), 8841191 (1996), 7550349 (1995)). The variant has been reported in individuals from multiple populations with a personal or family history of breast and/or ovarian cancer (PMIDs: 35377489 (2022), 33758026 (2022), 35039532 (2022), 35264596 (2022), 35356428 (2022), 35710434 (2022), 33646313 (2021), 32341426 (2020), 31528241 (2019), 31372034 (2019), 31159747 (2019), 30875412 (2019), 30630528 (2019), 30489631 (2019)) and prostate cancer (PMIDs: 33556450 (2021), 32338768 (2020), 31948886 (2020)). Functional studies report the variant disrupts proper protein function (PMID: 35459234 (2022)). Based on the available information, this variant is classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Glu23Valfs*17) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs386833395, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer, and pancreatic cancer (PMID: 9042909, 15994883, 22430266, 23658460, 24737347). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8571953, 8651293, 9042909, 9921907, 15994883, 22430266, 23658460, 24737347). This variant is also known as 185delAG or 187delAG. ClinVar contains an entry for this variant (Variation ID: 17662). For these reasons, this variant has been classified as Pathogenic.
Comment:
The BRCA1 c.68_69delAG; p.Glu23ValfsTer17 variant (rs386833395), also known as 185delAG, is a well known founder variant associated with breast, ovarian, and pancreatic cancer in the Ashkenazi Jewish population as well as other ethnic populations (Abeliovich 1997, Antoniou 2005, King 2003, Laitman 2019, Lucas 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 17662), and is found in the general population with an overall allele frequency of 0.02% (58/282442 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Glu23ValfsTer17 variant is considered to be pathogenic. [**Use the AJ BRCA template under BRCA NGS, OR Make sure to add the AJ recommendations from that template "If this individual is of Ashkenazi Jewish ancestry…"**] References: Abeliovich D et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet. 1997 Mar;60(3):505-14. Antoniou AC et al. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J Med Genet. 2005 Jul;42(7):602-3. King MC et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003 Oct 24;302(5645):643-6. Laitman Y et al. The spectrum of BRCA1 and BRCA2 pathogenic sequence variants in Middle Eastern, North African, and South European countries. Hum Mutat. 2019 Nov;40(11):e1-e23. Lucas AL et al. BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts. Cancer. 2014 Jul 1;120(13):1960-7.
Comment:
This variant deletes 2 nucleotides in exon 2 of the BRCA1 gene, causing a frameshift and a premature translational stop signal. This variant is also known as 185delAG and 187delAG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.96-1.14% minor allele frequency (PMID: 7550349, 8571953, 30152102). This variant has been reported in dozens of individuals and families affected with breast and ovarian cancer (PMID: 7894492, 7611277, 7837387, 8533757, 8531968, 8642955, 9042909, 9150153, 21643751, 30480775, 35020120). This variant also has been observed in individuals from diverse ethnicities in Africa, America, Asia and Europe (PMID: 8651293, 24312913). The risk of female breast cancer among carriers of this mutation is 55-83% by age 70, and the risk of ovarian cancer is 12-58% by age 70 (PMID: 9145676, 15994883, 22430266). A breast cancer case-control meta-analysis has detected this variant in 30/60436 cases and 8/53453 unaffected individuals with an odds ratio (OR) of 3.317 (95%CI 1.52 to 7.235) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001114). This variant has been identified in 58/282442 chromosomes (42/10368 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Variant summary: The BRCA1 c.68_69delAG (p.Glu23Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest is one of the most common Jewish founder mutations. Multiple publications have cited the variant in affected individuals. This variant was found in 29/120972 control chromosomes at a frequency of 0.0002397, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The c.68_69del (p.Glu23Valfs*17) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 14576434, 26718727, 21503673, 22430266, 23633455, 22752604, referred as c.185delAG in some publications]. This variant is a founder mutation in Ashkenazi Jews with a frequency of about 1% [PMID 14576434]. The variant has also been detected in patients with prostate [PMID 22516946] and pancreatic cancer [PMID 20711688, 24737347, 23658460, 26440929]. This one bp deletion in exon 2 results in a frameshift and the creation of a premature stop codon. Functional in vitro assays showed that this variant was deleterious [PMID 23867111]. This variant has been reported in 31 individuals from the ExAC database (http://exac.broadinstitute.org/variant/22-29091226-TA-T). This variant is thus classified as pathogenic
Comment:
The c.68_69del;p.(Glu23Valfs*17) is a null frameshift variant (NMD) in the BRCA1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17662; PMID: 7611277; PMID: 7894492; PMID: 14576434; PMID: 21503673; PMID: 22430266)PS4. The variant is present at low allele frequencies population databases (rs80357914 – gnomAD 0.001446%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
The c.68_69del variant in BRCA1 (also referred as c.185delAG) is an established pathogenic variant [ClinVar ID:17662] that is predicted (p.(Glu23fs)) to result in atruncated or absent BRCA1 protein due to nonsense mediated decay. The c.68_69del variant is a founder mutation in Ashkenazi Jewish population with a frequency of about 1% [PMID: 14576434]. The c.68_69del variant has been reported in multiple individuals with breast and/or ovarian, prostate, and pancreatic cancers [PMID:14576434, 20711688, 22516946, 23633455, 22752604]. Based on available evidence, this c.68_69del (p.(Glu23fs)) variant identified in BRCA1 is reported as Pathogenic.
Comment:
This variant deletes 2 nucleotides in exon 2 of the BRCA1 gene, causing a frameshift and a premature translational stop signal. This variant is also known as 185delAG and 187delAG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.96-1.14% minor allele frequency (PMID: 7550349, 8571953, 30152102). This variant has been reported in dozens of individuals and families affected with breast and ovarian cancer (PMID: 7894492, 7611277, 7837387, 8533757, 8531968, 8642955, 9042909, 9150153, 21643751, 30480775, 35020120). This variant also has been observed in individuals from diverse ethnicities in Africa, America, Asia and Europe (PMID: 8651293, 24312913). The risk of female breast cancer among carriers of this mutation is 55-83% by age 70, and the risk of ovarian cancer is 12-58% by age 70 (PMID: 9145676, 15994883, 22430266). A breast cancer case-control meta-analysis has detected this variant in 30/60436 cases and 8/53453 unaffected individuals with an odds ratio (OR) of 3.317 (95%CI 1.52 to 7.235) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001114). This variant has been identified in 58/282442 chromosomes (42/10368 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The c.68_69delAG (p.E23Vfs*17) alteration, located in exon 2 (coding exon 1) of the BRCA1 gene, consists of a deletion of 2 nucleotides from position 68 to 69, causing a translational frameshift with a predicted alternate stop codon after 17 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this variant has an overall frequency of 0.021% (58/282442) total alleles studied. The highest observed frequency was 0.405% (42/10368) of Ashkenazi Jewish alleles. This alteration is one of three well-characterized Ashkenazi Jewish founder mutations, with an overall carrier frequency of nearly 1% in this population (Struewing, 1995; Hartge, 1999). Average female breast cancer and ovarian cancer risks (by age 70) associated with this specific mutation have been estimated at 64% (range: 34-80%) and 14% (range: 2-24%), respectively (Antoniou, 2005). Additionally, this germline mutation has been reported in individuals of Ashkenazi Jewish descent with personal and/or family history of pancreatic cancer (Lucas, 2013; Lucas, 2014). It has also been identified in multiple Spanish hereditary breast and ovarian cancer families (Gabaldó Barrios, 2017). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
PVS1; PM5_PTC_Strong
Comment:
The frameshift c.68_69del (p.Glu23ValfsTer17) variant in the BRCA1 gene has been reported in a heterozygous state in individuals affected with Hereditary Breast and Ovarian Cancer (Petrucelli N et al. 2022; Rajagopal T et al., 2022). Functional assays showed this variant was deleterious (Bouwman P et al. 2013). The p.Glu23ValfsTer17 variant has an allele frequency of 0.02% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). This variant causes a frameshift starting with codon Glutamic Acid 23, changes this amino acid to Valine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Glu23ValfsTer17. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Criteria applied: PVS1,PS3,PS4_MOD,PM5_STR
Comment:
Criteria applied: PVS1,PS4
Comment:
BRCA1: PVS1, PM2, PS4:Moderate
Comment:
This sequence change deletes 2 nucleotides from exon 2 of the BRCA1 mRNA (c.68_69delAG), causing a frameshift after codon 23 and the creation of a premature translation stop signal 17 amino acid residues later – p.Glu23Valfs*17). This is expected to result in an absent or disrupted protein product. This variant, also known as BRCA1_185delAG or 187delAG, is one of three main pathogenic founder variants in the Ashkenazi Jewish population although it has been observed in individuals from other ethnicities as well (PMID: 23199084 ). This mutation has been described in the mutation database ClinVar(Variation ID: 17662). Therefore, this variant has been classified as pathogenic.
Comment:
The BRCA1 c.68_69delAG variant is predicted to result in a frameshift and premature protein termination (p.Glu23Valfs*17). This variant, also described as 185delAG or 187delAG in the literature, has been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC) (OMIM #604370). This is a recurrent variant among individuals of Spanish origin and is a founder variant in the Ashkenazi Jewish population, identified in about 1% of Ashkenazi Jewish individuals unselected for breast cancer (Gabaldó Barrios et al. 2017. PubMed ID: 28477318; Finkelman et al. 2012. PubMed ID: 22430266; Struewing et al. 1997. PubMed ID:9145676; Roa et al. 1996. PubMed ID:8841191). This variant is frequently observed in the Ashkenazi Jewish population in gnomad. This variant is also found in individuals of diverse ancestry at variable frequencies. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/17662/). In summary, this variant is interpreted as pathogenic.
Comment:
Converted during submission to Pathogenic.
Comment:
The p.Glu23ValfsX17 deletion variant is one of three known founder pathogenic mutations common to individuals of Ashkenazi Jewish descent (Petrucelli 1998). This deletion is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 23 and leads to a premature stop codon 17 codons downstream. This alteration is then predicted to lead to a truncated or absent protein product and loss of function. Loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic.
Comment:
Founder variant in Ashkenazi Jews; accounts for 72% of pathogenic variants in this population
Comment:
Variant interpreted as Pathogenic and reported on 12-11-2018 by Lab or GTR ID 505849. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Comment:
Variant reported in multiple GenomeConnect-Invitae Patient Insights Network participants by Lab Invitae. Variant interpreted as Pathogenic and reported, most recently, on 02-06-2021 and on 03-26-2018. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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loss_of_function_variant
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Bioinformatics dept., Datar Cancer Genetics Limited, India
Accession: SCV000583605.1
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Comment:
The c.68_69del variant in BRCA1 is a deletion of two nucleotides, predicted to encode a frameshift with consequent premature termination of the protein at codon 17 of the frameshift, or amino acid 39 (p.Glu23ValfsTer17). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA1, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA1 exon 3 (PM5_Strong (PTC)). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 32546644) (PS3 met). In summary, this variant meets the criteria to be classified as a Pathogenic variant variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PS3).
Comment:
The c.68_69delAG (p.Glu23ValfsTer17) variant, also commonly known as 185delAG, is a frameshift variant that is very well described in the literature as one of the most frequent variants found in breast cancer (Shattuck-Eidens et al. 1995; Offit et al. 1996). It was first identified in a study by Simard et al. (1994) in index cases from four unrelated Canadian families with hereditary breast and ovarian cancer (HBOC). Wang et al. (2012) conducted a meta-analysis of over 29 studies published between 2000 and 2010 and determined the overall frequency of the p.Glu23ValfsTer17 variant in 2128 breast cancer cases to be 0.072. The variant is one of three known common founder germline variants primarily found in individuals of Ashkenazi Jewish heritage (Struewing et al. 1997; Abeliovich et al. 1997; Laitman et al. 2013) and has been detected in 20% of Ashkenazi Jewish women diagnosed with breast cancer before age 42 years (Offit et al 1996). In the Ashkenazi Jewish population, the variant is associated with a risk of between 56% and 83% of breast cancer and of between 14% and 58% risk of ovarian cancer by the age of 70 (Struewing et al. 1997; Antoniou et al. 2005; Finkelman et al. 2012). The variant has been observed in individuals of other ethnicities (Wang et al. 2012; Laitman et al. 2013). The variant is reported at a frequency of 0.00042 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Based on the available evidence, the p.Glu23ValfsTer17 variant is classified as pathogenic for hereditary breast and ovarian cancer.
Comment:
This sequence change deletes 2 nucleotides from exon 2 of the BRCA1 mRNA (c.68_69delAG), causing a frameshift after codon 23 and the creation of a premature translation stop signal 17 amino acid residues later - p.(Glu23Valfs*17). This is expected to result in an absent or disrupted protein product.This variant, also known as BRCA1_185delAG or 187delAG, is one of three main pathogenic founder variants in the Ashkenazi Jewish population although it has been observed in individuals from other ethnicities as well (PMID: 23199084 ). This mutation has been described in the mutation database ClinVar(Variation ID: 17662).
Comment:
The p.Glu23ValfsX17 variant in BRCA1 has been reported in numerous individuals with hereditary breast and ovarian cancer (HBOC) and is a known pathogenic Ashkenazi Jewish founder variant (Struewing 1997 PMID: 9145676, Abeliovich 2013 PMID: 9042909). It has also been identified in 0.4% (42/10368) of Ashkenazi Jewish and 0.009% (11/128780) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that this frequency is low enough to be consistent with the frequency of HBOC in the general population. This frameshift variant is predicted to alter the protein's amino acid sequence beginning at position 23 and lead to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with HBOC. Additionally, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282348.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein and presence in multiple affected individuals. ACMG/AMP Criteria applied: PVS1, PS4_strong.
Comment:
The BRCA1 c.68_69del (p.Glu23ValfsTer17) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has a maximum subpopulation frequency of 0.41% in gnomAD v2.1.1, where it is primarily found in the Ashkenazi Jewish population (https://gnomad.broadinstitute.org/variant/17-41276044-ACT-A?dataset=gnomad_r2_1). This variant has been reported in multiple individuals with breast cancer and/or ovarian cancer (PMID: 14576434, 26718727, 21503673, 22430266, 23633455, 22752604), prostate (PMID: 22516946) and pancreatic cancer (PMID: 20711688, 24737347, 23658460, 26440929). It is a well-established pathogenic founder variant in the Ashkenazi Jewish population (PMID: 9042909, 22430266). This alteration is also known as 185delAG or 187delAG in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 185delAG or 187delAG; This variant is associated with the following publications: (PMID: 18594935, 26071757, 26221963, 27259235, 28049106, 26822237, 29176636, 31948886, 22703879, 22535016, 22516946, 22009639, 23633455, 23658460, 22763381, 23086583, 19906413, 21503673, 22430266, 20711688, 22752604, 22006311, 7611277, 23867111, 25556971, 24737347, 26440929, 26689913, 26641009, 27553291, 23788959, 26718727, 26681312, 27836010, 29321669, 27062684, 28528518, 11802208, 28477318, 29339979, 29752822, 28324225, 27989354, 29907814, 29431110, 29560538, 26556299, 10464624, 29470806, 28390335, 28993434, 26357657, 29161300, 30702160, 30067863, 30152102, 30630528, 30122538, 30186769, 30720243, 30322717, 30093976, 31159747, 30113427, 31372034, 30489631, 30612635, 31454914, 31528241, 29625052, 31447099, 31980526, 34308366, 33646313, 10739756, 10733239, 11597388, 9042909, 12220453, 31589614, 32341426, 9634504, 10885601, 32719484, 33556450, 12491828, 32338768, 30875412, 30787465, 16030426, 33224455)
Comment:
This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.0041 (42/10368 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported as one of the common pathogenic BRCA founder variants in the Ashkenazi Jewish population (PMIDs: 22430266 (2012), 14576434 (2003), 8841191 (1996), 7550349 (1995)). The variant has been reported in individuals from multiple populations with a personal or family history of breast and/or ovarian cancer (PMIDs: 35377489 (2022), 33758026 (2022), 35039532 (2022), 35264596 (2022), 35356428 (2022), 35710434 (2022), 33646313 (2021), 32341426 (2020), 31528241 (2019), 31372034 (2019), 31159747 (2019), 30875412 (2019), 30630528 (2019), 30489631 (2019)) and prostate cancer (PMIDs: 33556450 (2021), 32338768 (2020), 31948886 (2020)). Functional studies report the variant disrupts proper protein function (PMID: 35459234 (2022)). Based on the available information, this variant is classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Glu23Valfs*17) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs386833395, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer, and pancreatic cancer (PMID: 9042909, 15994883, 22430266, 23658460, 24737347). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8571953, 8651293, 9042909, 9921907, 15994883, 22430266, 23658460, 24737347). This variant is also known as 185delAG or 187delAG. ClinVar contains an entry for this variant (Variation ID: 17662). For these reasons, this variant has been classified as Pathogenic.
Comment:
The BRCA1 c.68_69delAG; p.Glu23ValfsTer17 variant (rs386833395), also known as 185delAG, is a well known founder variant associated with breast, ovarian, and pancreatic cancer in the Ashkenazi Jewish population as well as other ethnic populations (Abeliovich 1997, Antoniou 2005, King 2003, Laitman 2019, Lucas 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 17662), and is found in the general population with an overall allele frequency of 0.02% (58/282442 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Glu23ValfsTer17 variant is considered to be pathogenic. [**Use the AJ BRCA template under BRCA NGS, OR Make sure to add the AJ recommendations from that template "If this individual is of Ashkenazi Jewish ancestry…"**] References: Abeliovich D et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet. 1997 Mar;60(3):505-14. Antoniou AC et al. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J Med Genet. 2005 Jul;42(7):602-3. King MC et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003 Oct 24;302(5645):643-6. Laitman Y et al. The spectrum of BRCA1 and BRCA2 pathogenic sequence variants in Middle Eastern, North African, and South European countries. Hum Mutat. 2019 Nov;40(11):e1-e23. Lucas AL et al. BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts. Cancer. 2014 Jul 1;120(13):1960-7.
Comment:
This variant deletes 2 nucleotides in exon 2 of the BRCA1 gene, causing a frameshift and a premature translational stop signal. This variant is also known as 185delAG and 187delAG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.96-1.14% minor allele frequency (PMID: 7550349, 8571953, 30152102). This variant has been reported in dozens of individuals and families affected with breast and ovarian cancer (PMID: 7894492, 7611277, 7837387, 8533757, 8531968, 8642955, 9042909, 9150153, 21643751, 30480775, 35020120). This variant also has been observed in individuals from diverse ethnicities in Africa, America, Asia and Europe (PMID: 8651293, 24312913). The risk of female breast cancer among carriers of this mutation is 55-83% by age 70, and the risk of ovarian cancer is 12-58% by age 70 (PMID: 9145676, 15994883, 22430266). A breast cancer case-control meta-analysis has detected this variant in 30/60436 cases and 8/53453 unaffected individuals with an odds ratio (OR) of 3.317 (95%CI 1.52 to 7.235) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001114). This variant has been identified in 58/282442 chromosomes (42/10368 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Variant summary: The BRCA1 c.68_69delAG (p.Glu23Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest is one of the most common Jewish founder mutations. Multiple publications have cited the variant in affected individuals. This variant was found in 29/120972 control chromosomes at a frequency of 0.0002397, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The c.68_69del (p.Glu23Valfs*17) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 14576434, 26718727, 21503673, 22430266, 23633455, 22752604, referred as c.185delAG in some publications]. This variant is a founder mutation in Ashkenazi Jews with a frequency of about 1% [PMID 14576434]. The variant has also been detected in patients with prostate [PMID 22516946] and pancreatic cancer [PMID 20711688, 24737347, 23658460, 26440929]. This one bp deletion in exon 2 results in a frameshift and the creation of a premature stop codon. Functional in vitro assays showed that this variant was deleterious [PMID 23867111]. This variant has been reported in 31 individuals from the ExAC database (http://exac.broadinstitute.org/variant/22-29091226-TA-T). This variant is thus classified as pathogenic
Comment:
The c.68_69del;p.(Glu23Valfs*17) is a null frameshift variant (NMD) in the BRCA1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17662; PMID: 7611277; PMID: 7894492; PMID: 14576434; PMID: 21503673; PMID: 22430266)PS4. The variant is present at low allele frequencies population databases (rs80357914 – gnomAD 0.001446%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
The c.68_69del variant in BRCA1 (also referred as c.185delAG) is an established pathogenic variant [ClinVar ID:17662] that is predicted (p.(Glu23fs)) to result in atruncated or absent BRCA1 protein due to nonsense mediated decay. The c.68_69del variant is a founder mutation in Ashkenazi Jewish population with a frequency of about 1% [PMID: 14576434]. The c.68_69del variant has been reported in multiple individuals with breast and/or ovarian, prostate, and pancreatic cancers [PMID:14576434, 20711688, 22516946, 23633455, 22752604]. Based on available evidence, this c.68_69del (p.(Glu23fs)) variant identified in BRCA1 is reported as Pathogenic.
Comment:
This variant deletes 2 nucleotides in exon 2 of the BRCA1 gene, causing a frameshift and a premature translational stop signal. This variant is also known as 185delAG and 187delAG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.96-1.14% minor allele frequency (PMID: 7550349, 8571953, 30152102). This variant has been reported in dozens of individuals and families affected with breast and ovarian cancer (PMID: 7894492, 7611277, 7837387, 8533757, 8531968, 8642955, 9042909, 9150153, 21643751, 30480775, 35020120). This variant also has been observed in individuals from diverse ethnicities in Africa, America, Asia and Europe (PMID: 8651293, 24312913). The risk of female breast cancer among carriers of this mutation is 55-83% by age 70, and the risk of ovarian cancer is 12-58% by age 70 (PMID: 9145676, 15994883, 22430266). A breast cancer case-control meta-analysis has detected this variant in 30/60436 cases and 8/53453 unaffected individuals with an odds ratio (OR) of 3.317 (95%CI 1.52 to 7.235) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001114). This variant has been identified in 58/282442 chromosomes (42/10368 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The c.68_69delAG (p.E23Vfs*17) alteration, located in exon 2 (coding exon 1) of the BRCA1 gene, consists of a deletion of 2 nucleotides from position 68 to 69, causing a translational frameshift with a predicted alternate stop codon after 17 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this variant has an overall frequency of 0.021% (58/282442) total alleles studied. The highest observed frequency was 0.405% (42/10368) of Ashkenazi Jewish alleles. This alteration is one of three well-characterized Ashkenazi Jewish founder mutations, with an overall carrier frequency of nearly 1% in this population (Struewing, 1995; Hartge, 1999). Average female breast cancer and ovarian cancer risks (by age 70) associated with this specific mutation have been estimated at 64% (range: 34-80%) and 14% (range: 2-24%), respectively (Antoniou, 2005). Additionally, this germline mutation has been reported in individuals of Ashkenazi Jewish descent with personal and/or family history of pancreatic cancer (Lucas, 2013; Lucas, 2014). It has also been identified in multiple Spanish hereditary breast and ovarian cancer families (Gabaldó Barrios, 2017). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
PVS1; PM5_PTC_Strong
Comment:
The frameshift c.68_69del (p.Glu23ValfsTer17) variant in the BRCA1 gene has been reported in a heterozygous state in individuals affected with Hereditary Breast and Ovarian Cancer (Petrucelli N et al. 2022; Rajagopal T et al., 2022). Functional assays showed this variant was deleterious (Bouwman P et al. 2013). The p.Glu23ValfsTer17 variant has an allele frequency of 0.02% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). This variant causes a frameshift starting with codon Glutamic Acid 23, changes this amino acid to Valine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Glu23ValfsTer17. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Criteria applied: PVS1,PS3,PS4_MOD,PM5_STR
Comment:
Criteria applied: PVS1,PS4
Comment:
BRCA1: PVS1, PM2, PS4:Moderate
Comment:
This sequence change deletes 2 nucleotides from exon 2 of the BRCA1 mRNA (c.68_69delAG), causing a frameshift after codon 23 and the creation of a premature translation stop signal 17 amino acid residues later – p.Glu23Valfs*17). This is expected to result in an absent or disrupted protein product. This variant, also known as BRCA1_185delAG or 187delAG, is one of three main pathogenic founder variants in the Ashkenazi Jewish population although it has been observed in individuals from other ethnicities as well (PMID: 23199084 ). This mutation has been described in the mutation database ClinVar(Variation ID: 17662). Therefore, this variant has been classified as pathogenic.
Comment:
The BRCA1 c.68_69delAG variant is predicted to result in a frameshift and premature protein termination (p.Glu23Valfs*17). This variant, also described as 185delAG or 187delAG in the literature, has been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC) (OMIM #604370). This is a recurrent variant among individuals of Spanish origin and is a founder variant in the Ashkenazi Jewish population, identified in about 1% of Ashkenazi Jewish individuals unselected for breast cancer (Gabaldó Barrios et al. 2017. PubMed ID: 28477318; Finkelman et al. 2012. PubMed ID: 22430266; Struewing et al. 1997. PubMed ID:9145676; Roa et al. 1996. PubMed ID:8841191). This variant is frequently observed in the Ashkenazi Jewish population in gnomad. This variant is also found in individuals of diverse ancestry at variable frequencies. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/17662/). In summary, this variant is interpreted as pathogenic.
Comment:
Converted during submission to Pathogenic.
Comment:
The p.Glu23ValfsX17 deletion variant is one of three known founder pathogenic mutations common to individuals of Ashkenazi Jewish descent (Petrucelli 1998). This deletion is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 23 and leads to a premature stop codon 17 codons downstream. This alteration is then predicted to lead to a truncated or absent protein product and loss of function. Loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic.
Comment:
Founder variant in Ashkenazi Jews; accounts for 72% of pathogenic variants in this population
Comment:
Variant interpreted as Pathogenic and reported on 12-11-2018 by Lab or GTR ID 505849. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Comment:
Variant reported in multiple GenomeConnect-Invitae Patient Insights Network participants by Lab Invitae. Variant interpreted as Pathogenic and reported, most recently, on 02-06-2021 and on 03-26-2018. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Featuring BRCA1 and BRCA2 germline mutational landscape from Asturias (North Spain). | Pitiot AS | Clinical genetics | 2024 | PMID: 38922859 |
| BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. | Adam MP | - | 2023 | PMID: 20301425 |
| Spectrum of germline pathogenic variants using a targeted next generation sequencing panel and genotype-phenotype correlations in patients with suspected hereditary breast cancer at an academic medical centre in Pakistan. | Akbar F | Hereditary cancer in clinical practice | 2022 | PMID: 35710434 |
| Prevalence of Clinically Relevant Germline BRCA Variants in a Large Unselected South African Breast and Ovarian Cancer Cohort: A Public Sector Experience. | Van der Merwe NC | Frontiers in genetics | 2022 | DOI: 10.3389/fgene.2022.834265 |
| Pathogenic BRCA1 variants disrupt PLK1-regulation of mitotic spindle orientation. | He Z | Nature communications | 2022 | PMID: 35459234 |
| Chasing the origin of 23 recurrent BRCA1 mutations in Pakistani breast and ovarian cancer patients. | Rashid MU | International journal of cancer | 2022 | PMID: 35377489 |
| Germline Mutation Analysis in Sporadic Breast Cancer Cases With Clinical Correlations. | Ajaz S | Frontiers in genetics | 2022 | PMID: 35356428 |
| Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. | Guindalini RSC | Scientific reports | 2022 | PMID: 35264596 |
| Value of the loss of heterozygosity to BRCA1 variant classification. | Santana Dos Santos E | NPJ breast cancer | 2022 | PMID: 35039532 |
| Analysis of pathogenic variants in BRCA1 and BRCA2 genes using next-generation sequencing in women with triple negative breast cancer from South India. | Rajagopal T | Molecular biology reports | 2022 | PMID: 35020120 |
| High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer. | Evans DG | Journal of medical genetics | 2022 | PMID: 33758026 |
| A comprehensive reference for BRCA1/2 genes pathogenic variants in Iran: published, unpublished and novel. | Majidzadeh-A K | Familial cancer | 2022 | PMID: 33754277 |
| Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors. | Fiala EM | Nature cancer | 2021 | PMID: 34308366 |
| Gene Sequencing for Pathogenic Variants Among Adults With Breast and Ovarian Cancer in the Caribbean. | George SHL | JAMA network open | 2021 | PMID: 33646313 |
| Management of a Prostate Cancer Patient With Inherited Germline BRCA1 and BRCA2 Mutations: A Case Report. | Hemal S | Urology | 2021 | PMID: 33556450 |
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Germline BRCA1 mutated esophageal squamous cell carcinoma. | Starr J | Rare tumors | 2020 | PMID: 33224455 |
| Population genetic screening efficiently identifies carriers of autosomal dominant diseases. | Grzymski JJ | Nature medicine | 2020 | PMID: 32719484 |
| Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes. | De Talhouet S | Scientific reports | 2020 | PMID: 32341426 |
| Rare germline genetic variants and risk of aggressive prostate cancer. | Nguyen-Dumont T | International journal of cancer | 2020 | PMID: 32338768 |
| Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
| Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer. | Wu Y | European urology oncology | 2020 | PMID: 31948886 |
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| Spectrum and prevalence of BRCA1/2 germline mutations in Pakistani breast cancer patients: results from a large comprehensive study. | Rashid MU | Hereditary cancer in clinical practice | 2019 | PMID: 31528241 |
| Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
| Frequency of germline mutations in BRCA1 and BRCA2 in ovarian cancer patients and their effect on treatment outcome. | Ashour M | Cancer management and research | 2019 | PMID: 31372034 |
| Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
| Discoveries beyond BRCA1/2: Multigene testing in an Asian multi-ethnic cohort suspected of hereditary breast cancer syndrome in the real world. | Ow SGW | PloS one | 2019 | PMID: 30875412 |
| Toward automation of germline variant curation in clinical cancer genetics. | Ravichandran V | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30787465 |
| High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering. | Soussi T | Human mutation | 2019 | PMID: 30720243 |
| Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients. | Bhaskaran SP | International journal of cancer | 2019 | PMID: 30702160 |
| Population and breast cancer patients' analysis reveals the diversity of genomic variation of the BRCA genes in the Mexican population. | Fernández-Lopez JC | Human genomics | 2019 | PMID: 30630528 |
| Uterine cancer in Jewish Israeli BRCA1/2 mutation carriers. | Laitman Y | Cancer | 2019 | PMID: 30489631 |
| Prevalence of nonfounder BRCA1/2 mutations in Ashkenazi Jewish patients presenting for genetic testing at a hereditary breast and ovarian cancer center. | Frey MK | Cancer | 2019 | PMID: 30480775 |
| Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. | Li JY | International journal of cancer | 2019 | PMID: 29752822 |
| GEMO, a National Resource to Study Genetic Modifiers of Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Pathogenic Variant Carriers. | Lesueur F | Frontiers in oncology | 2018 | PMID: 30430080 |
| Germline pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
| BRCA1 and BRCA2 Mutations Other Than the Founder Alleles Among Ashkenazi Jewish in the Population of Argentina. | Solano AR | Frontiers in oncology | 2018 | PMID: 30186769 |
| Hereditary cancer screening: Case reports and review of literature on ten Ashkenazi Jewish founder mutations. | Cox DM | Molecular genetics & genomic medicine | 2018 | PMID: 30152102 |
| Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot. | Sapp JC | American journal of human genetics | 2018 | PMID: 30122538 |
| Germline Variants and Risk for Pancreatic Cancer: A Systematic Review and Emerging Concepts. | Zhan W | Pancreas | 2018 | PMID: 30113427 |
| Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. | Chan GHJ | Oncotarget | 2018 | PMID: 30093976 |
| Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma. | Brand R | Cancer | 2018 | PMID: 30067863 |
| The germline mutational landscape of BRCA1 and BRCA2 in Brazil. | Palmero EI | Scientific reports | 2018 | PMID: 29907814 |
| Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
| Mutational analysis of candidate genes in Israeli male breast cancer cases. | Schayek H | Breast cancer research and treatment | 2018 | PMID: 29560538 |
| Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. | Singh J | Breast cancer research and treatment | 2018 | PMID: 29470806 |
| Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
| The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants. | Reuter MS | CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne | 2018 | PMID: 29431110 |
| BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. | Heramb C | Hereditary cancer in clinical practice | 2018 | PMID: 29339979 |
| Phenotypic characteristics of colorectal cancer in BRCA1/2 mutation carriers. | Grinshpun A | European journal of human genetics : EJHG | 2018 | PMID: 29321669 |
| Genetic and clinical characteristics in Japanese hereditary breast and ovarian cancer: first report after establishment of HBOC registration system in Japan. | Arai M | Journal of human genetics | 2018 | PMID: 29176636 |
| Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia. | Wen WX | Journal of medical genetics | 2018 | PMID: 28993434 |
| A multi-gene panel study in hereditary breast and ovarian cancer in Colombia. | Cock-Rada AM | Familial cancer | 2018 | PMID: 28528518 |
| BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population? | Alemar B | PloS one | 2017 | PMID: 29161300 |
| Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
| Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical-pathological features in BRCA carriers and non-carriers. | Gabaldó Barrios X | Familial cancer | 2017 | PMID: 28477318 |
| A case series of three Sri Lankan families with hereditary breast and ovarian cancer syndrome due to pathogenic germline mutations in the BRCA1 gene. | Sirisena ND | The Ceylon medical journal | 2017 | PMID: 28390335 |
| Spectrum of genetic variants of BRCA1 and BRCA2 in a German single center study. | Meisel C | Archives of gynecology and obstetrics | 2017 | PMID: 28324225 |
| Linking uterine serous carcinoma to BRCA1/2-associated cancer syndrome: A meta-analysis and case report. | de Jonge MM | European journal of cancer (Oxford, England : 1990) | 2017 | PMID: 28049106 |
| Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. | Na R | European urology | 2017 | PMID: 27989354 |
| Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. | Rebbeck TR | Breast cancer research : BCR | 2016 | PMID: 27836010 |
| High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients. | Rashid MU | BMC cancer | 2016 | PMID: 27553291 |
| Germline BRCA1 mutation reprograms breast epithelial cell metabolism towards mitochondrial-dependent biosynthesis: evidence for metformin-based "starvation" strategies in BRCA1 carriers. | Cuyàs E | Oncotarget | 2016 | PMID: 27259235 |
| Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study. | Azzollini J | European journal of internal medicine | 2016 | PMID: 27062684 |
| Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors. | Parsons DW | JAMA oncology | 2016 | PMID: 26822237 |
| Genetic characterization of early onset ovarian carcinoma. | Bernards SS | Gynecologic oncology | 2016 | PMID: 26718727 |
| Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
| Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia. | Churpek JE | Cancer | 2016 | PMID: 26641009 |
| Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. | Schrader KA | JAMA oncology | 2016 | PMID: 26556299 |
| Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
| Identification of germline genetic mutations in patients with pancreatic cancer. | Salo-Mullen EE | Cancer | 2015 | PMID: 26440929 |
| BRCA1 185delAG Mutation Enhances Interleukin-1β Expression in Ovarian Surface Epithelial Cells. | Woolery KT | BioMed research international | 2015 | PMID: 26357657 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| Prevalence and impact of founder mutations in hereditary breast cancer in Latin America. | Ashton-Prolla P | Genetics and molecular biology | 2014 | PMID: 24764757 |
| BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts. | Lucas AL | Cancer | 2014 | PMID: 24737347 |
| A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. | Karami F | BioMed research international | 2013 | PMID: 24312913 |
| The different impact of BRCA mutations on the survival of epithelial ovarian cancer patients: a retrospective single-center experience. | Lorusso D | Oncology | 2013 | PMID: 23941904 |
| A high-throughput functional complementation assay for classification of BRCA1 missense variants. | Bouwman P | Cancer discovery | 2013 | PMID: 23867111 |
| Localization of BRCA1 protein in breast cancer tissue and cell lines with mutations. | Tulchin N | Cancer cell international | 2013 | PMID: 23855721 |
| Prevalence of the BRCA1 c.68_69delAG (BIC: 185delAG) mutation in women with breast cancer from north-central Poland and a review of the literature on other regions of the country. | Hartwig M | Contemporary oncology (Poznan, Poland) | 2013 | PMID: 23788959 |
| Mutational analysis of BRCA1 and BRCA2 in hereditary breast and ovarian cancer families from Asturias (Northern Spain). | Blay P | BMC cancer | 2013 | PMID: 23683081 |
| High prevalence of BRCA1 and BRCA2 germline mutations with loss of heterozygosity in a series of resected pancreatic adenocarcinoma and other neoplastic lesions. | Lucas AL | Clinical cancer research : an official journal of the American Association for Cancer Research | 2013 | PMID: 23658460 |
| Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations. | George J | Clinical cancer research : an official journal of the American Association for Cancer Research | 2013 | PMID: 23633455 |
| PGD for hereditary breast and ovarian cancer: the route to universal tests for BRCA1 and BRCA2 mutation carriers. | Drüsedau M | European journal of human genetics : EJHG | 2013 | PMID: 23531862 |
| Prevalence and type of BRCA mutations in Hispanics undergoing genetic cancer risk assessment in the southwestern United States: a report from the Clinical Cancer Genetics Community Research Network. | Weitzel JN | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2013 | PMID: 23233716 |
| Absence of loss of heterozygosity of BRCA1 in a renal tumor from a BRCA1 germline mutation carrier. | Alanee S | Familial cancer | 2013 | PMID: 23086583 |
| Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations. | Laitman Y | European journal of human genetics : EJHG | 2013 | PMID: 22763381 |
| BRCA1/BRCA2 gene mutations/SNPs and BRCA1 haplotypes in early-onset breast cancer patients of Indian ethnicity. | Juwle A | Medical oncology (Northwood, London, England) | 2012 | PMID: 22752604 |
| Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
| Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management. | Heidemann S | Breast cancer research and treatment | 2012 | PMID: 22535016 |
| Germline BRCA1 mutations increase prostate cancer risk. | Leongamornlert D | British journal of cancer | 2012 | PMID: 22516946 |
| Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. | Finkelman BS | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22430266 |
| Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. | Bolton KL | JAMA | 2012 | PMID: 22274685 |
| Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ. | Bayraktar S | Cancer | 2012 | PMID: 22009639 |
| Common BRCA1 and BRCA2 mutations in breast cancer families: a meta-analysis from systematic review. | Wang F | Molecular biology reports | 2012 | PMID: 21643751 |
| Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. | Walsh T | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 22006311 |
| Prevalence of the most frequent BRCA1 mutations in Polish population. | Brozek I | Journal of applied genetics | 2011 | PMID: 21503673 |
| Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. | Zhang S | Gynecologic oncology | 2011 | PMID: 21324516 |
| Comprehensive genetic characterization of hereditary breast/ovarian cancer families from Slovakia. | Konecny M | Breast cancer research and treatment | 2011 | PMID: 21203900 |
| Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population. | Lavie O | Annals of oncology : official journal of the European Society for Medical Oncology | 2011 | PMID: 20924075 |
| A 67-year-old woman with BRCA 1 mutation associated with pancreatic adenocarcinoma. | Lowery M | Journal of gastrointestinal cancer | 2011 | PMID: 20711688 |
| Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. | Janavičius R | The EPMA journal | 2010 | PMID: 23199084 |
| AKT and p21 WAF1/CIP1 as potential genistein targets in BRCA1-mutant human breast cancer cell lines. | Privat M | Anticancer research | 2010 | PMID: 20651350 |
| Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. | Borg A | Human mutation | 2010 | PMID: 20104584 |
| BRCA1 185delAG mutant protein, BRAt, up-regulates maspin in ovarian epithelial cells. | O'Donnell JD | Gynecologic oncology | 2010 | PMID: 19906413 |
| Age-dependent penetrance of different germline mutations in the BRCA1 gene. | Al-Mulla F | Journal of clinical pathology | 2009 | PMID: 19329713 |
| High frequency of TP53 mutation in BRCA1 and sporadic basal-like carcinomas but not in BRCA1 luminal breast tumors. | Manié E | Cancer research | 2009 | PMID: 19147582 |
| Germline BRCA1 mutations predispose to pancreatic adenocarcinoma. | Al-Sukhni W | Human genetics | 2008 | PMID: 18762988 |
| BRCA1 185delAG truncation protein, BRAt, amplifies caspase-mediated apoptosis in ovarian cells. | O'Donnell JD | In vitro cellular & developmental biology. Animal | 2008 | PMID: 18594935 |
| Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. | Fackenthal JD | Nature reviews. Cancer | 2007 | PMID: 18034184 |
| Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. | Ramus SJ | Human mutation | 2007 | PMID: 17688236 |
| Founder mutations in BRCA1 and BRCA2 genes. | Ferla R | Annals of oncology : official journal of the European Society for Medical Oncology | 2007 | PMID: 17591843 |
| Cancer risks in carriers of the BRCA1/2 Ashkenazi founder mutations. | Kadouri L | Journal of medical genetics | 2007 | PMID: 17307836 |
| The 185delAG mutation (c.68_69delAG) in the BRCA1 gene triggers translation reinitiation at a downstream AUG codon. | Buisson M | Human mutation | 2006 | PMID: 16941470 |
| High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area. | Pohlreich P | Breast cancer research : BCR | 2005 | PMID: 16168118 |
| Differences in the characteristics of families with BRCA1 and BRCA2 mutations in Israel. | Rennert G | European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP) | 2005 | PMID: 16030426 |
| Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. | Antoniou AC | Journal of medical genetics | 2005 | PMID: 15994883 |
| Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations. | McGuire V | American journal of epidemiology | 2004 | PMID: 15383404 |
| BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian cancer in the Czech Republic. | Foretova L | Human mutation | 2004 | PMID: 15024741 |
| Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. | King MC | Science (New York, N.Y.) | 2003 | PMID: 14576434 |
| Mutations of the BRCA1 gene in hereditary breast and ovarian cancer in the Czech Republic. | Pohlreich P | Medical principles and practice : international journal of the Kuwait University, Health Science Centre | 2003 | PMID: 12566964 |
| [Frequency of the 185delAG mutation in the BRCA1 gene in Chilean healthy women with family history of breast cancer]. | Jara L | Revista medica de Chile | 2002 | PMID: 12491828 |
| Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. | Satagopan JM | Clinical cancer research : an official journal of the American Association for Cancer Research | 2002 | PMID: 12473589 |
| A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian cancer families. | Phelan CM | Human mutation | 2002 | PMID: 12402332 |
| Haplotype analysis of a BRCA1: 185delAG mutation in a Chilean family supports its Ashkenazi origins. | Ah Mew N | Clinical genetics | 2002 | PMID: 12220453 |
| Cancer incidence in a population of Jewish women at risk of ovarian cancer. | Liede A | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2002 | PMID: 11896106 |
| Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. | Frank TS | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2002 | PMID: 11896095 |
| Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing. | de la Hoya M | International journal of cancer | 2002 | PMID: 11802208 |
| Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families. | Verhoog LC | European journal of cancer (Oxford, England : 1990) | 2001 | PMID: 11597388 |
| The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in Australian Ashkenazi Jews: implications for the generality of U.S. population data. | Bahar AY | Cancer | 2001 | PMID: 11466700 |
| The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. | Satagopan JM | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2001 | PMID: 11352856 |
| Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. | Risch HA | American journal of human genetics | 2001 | PMID: 11179017 |
| Significantly lower rates of BRCA1/BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer. | Gershoni-Baruch R | European journal of cancer (Oxford, England : 1990) | 2000 | PMID: 10885601 |
| BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. | Moslehi R | American journal of human genetics | 2000 | PMID: 10739756 |
| An unaffected individual from a breast/ovarian cancer family with germline mutations in both BRCA1 and BRCA2. | Moslehi R | Clinical genetics | 2000 | PMID: 10733239 |
| The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. | Hartge P | American journal of human genetics | 1999 | PMID: 10090881 |
| Identification of the 185delAG BRCA1 mutation in a Spanish Gypsy population. | Díez O | Human genetics | 1998 | PMID: 9921907 |
| BRCA1 gene mutations in women with papillary serous carcinoma of the peritoneum. | Bandera CA | Obstetrics and gynecology | 1998 | PMID: 9764635 |
| Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. | Fodor FH | American journal of human genetics | 1998 | PMID: 9634504 |
| Molecular evidence for multifocal papillary serous carcinoma of the peritoneum in patients with germline BRCA1 mutations. | Schorge JO | Journal of the National Cancer Institute | 1998 | PMID: 9625172 |
| The 185delAG BRCA1 mutation originated before the dispersion of Jews in the diaspora and is not limited to Ashkenazim. | Bar-Sade RB | Human molecular genetics | 1998 | PMID: 9536083 |
| BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and ovarian cancer. | Schubert EL | Genetic testing | 1997 | PMID: 10464624 |
| Could the 185delAG BRCA1 mutation be an ancient Jewish mutation? | Bar-Sade RB | European journal of human genetics : EJHG | 1997 | PMID: 9450187 |
| Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. | Levy-Lahad E | American journal of human genetics | 1997 | PMID: 9150153 |
| The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. | Struewing JP | The New England journal of medicine | 1997 | PMID: 9145676 |
| The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. | Abeliovich D | American journal of human genetics | 1997 | PMID: 9042909 |
| Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. | Roa BB | Nature genetics | 1996 | PMID: 8841191 |
| Truncation at conserved terminal regions of BRCA1 protein is associated with highly proliferating hereditary breast cancers. | Sobol H | Cancer research | 1996 | PMID: 8764110 |
| Two distinct origins of a common BRCA1 mutation in breast-ovarian cancer families: a genetic study of 15 185delAG-mutation kindreds. | Berman DB | American journal of human genetics | 1996 | PMID: 8651293 |
| Germline BRCA1 185delAG mutations in Jewish women with breast cancer. | Offit K | Lancet (London, England) | 1996 | PMID: 8642955 |
| Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. | Neuhausen SL | American journal of human genetics | 1996 | PMID: 8571953 |
| Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer. | FitzGerald MG | The New England journal of medicine | 1996 | PMID: 8531968 |
| Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families. | Friedman LS | American journal of human genetics | 1995 | PMID: 8533757 |
| A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. | Shattuck-Eidens D | JAMA | 1995 | PMID: 7837387 |
| Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer. | Struewing JP | American journal of human genetics | 1995 | PMID: 7611277 |
| The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. | Struewing JP | Nature genetics | 1995 | PMID: 7550349 |
| Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. | Simard J | Nature genetics | 1994 | PMID: 7894492 |
| Family is not Ashkenazi Jewish. | - | - | - | - |
| http://lgdfm3.ncifcrf.gov/bic/BIC.html | - | - | - | - |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA1 | - | - | - | - |
| http://www.umd.be/BRCA1/ | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8cc9bd83-9b2d-4a38-ba40-c2010955350d | - | - | - | - |
| Strewing et al 1995 | - | - | - | - |
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Text-mined citations for rs80357914 ...
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Record last updated Nov 03, 2024
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