ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.8537_8538del (p.Glu2846fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.8537_8538del (p.Glu2846fs)
Variation ID: 9328 Accession: VCV000009328.41
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 13q13.1 13: 32371001-32371002 (GRCh38) [ NCBI UCSC ] 13: 32945138-32945139 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 19, 2014 May 1, 2024 Sep 8, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.8537_8538del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Glu2846fs frameshift NM_000059.3:c.8533_8534del NM_000059.3:c.8533_8534delAG NM_000059.3:c.8537_8538delAG NC_000013.11:g.32371001AG[2] NC_000013.10:g.32945138AG[2] NG_012772.3:g.60522AG[2] LRG_293:g.60522AG[2] U43746.1:n.8765_8766delAG - Protein change
- E2846fs
- Other names
- 8761delAG
- 8765delAG
- Canonical SPDI
- NC_000013.11:32371000:AGAGAG:AGAG
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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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 | ||
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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. |
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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18723 | 18881 |
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. |
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Pathogenic (8) |
reviewed by expert panel
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Sep 8, 2016 | RCV000009915.30 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000045550.35 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 31, 2023 | RCV000131085.20 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Nov 29, 2022 | RCV000160308.22 | |
Pathogenic (3) |
criteria provided, single submitter
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Jun 16, 2023 | RCV000735482.16 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001353461.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 4, 2023 | RCV003460447.1 |
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. |
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Pathogenic
(Sep 08, 2016)
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reviewed by expert panel
Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000301287.2
First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
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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: SCV000588121.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
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Pathogenic
(Feb 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271336.3
First in ClinVar: May 29, 2016 Last updated: Dec 26, 2017 |
Comment:
The p.Glu2846fs variant in BRCA2 is a well-established pathogenic founder varian t for several populations, including French Canadians, Jewish-Yemenites, and Nor thern Sardinian (Tonin 1998, … (more)
The p.Glu2846fs variant in BRCA2 is a well-established pathogenic founder varian t for several populations, including French Canadians, Jewish-Yemenites, and Nor thern Sardinian (Tonin 1998, Lerer 1998, Ferla 2007). This variant has been ide ntified in 1/66688 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs80359716). This frequency is low enou gh to be consistent with the frequency of hereditary breast and ovarian cancer ( HBOC) in the general population. This variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning at position 2846 and leads to a premature termination codon 22 amino acids downstream. This alteratio n is then predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 function is an established disease mechanism in HBOC. In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosom al dominant manner. (less)
Number of individuals with the variant: 2
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Pathogenic
(Jul 23, 2021)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503465.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Jun 03, 2022)
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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: SCV000916958.2
First in ClinVar: Jun 03, 2019 Last updated: Aug 08, 2022 |
Comment:
Variant summary: BRCA2 c.8537_8538delAG (p.Glu2846GlyfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: BRCA2 c.8537_8538delAG (p.Glu2846GlyfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251142 control chromosomes. c.8537_8538delAG has been reported in the literature in many individuals and families affected with Hereditary Breast And Ovarian Cancer Syndrome (example Phelan_1996, Machackova_2008, Ghadirian_2014) including 76 patients from the BIC database. It is commonly reported as a pathogenic variant in French Canadian, Yemenite Jewish, and Northern Sardinian populations (example Lerer_1998, Manning_2001, Palomba_ 2007). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories and reputable databases have classified this variant as pathogenic in ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004213708.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Nov 29, 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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Revvity Omics, Revvity
Accession: SCV003813739.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jun 16, 2023)
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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
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV000219410.8
First in ClinVar: Mar 29, 2015 Last updated: Feb 04, 2024 |
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Pathogenic
(May 31, 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
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000683979.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 2 nucleotides in exon 20 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 2 nucleotides in exon 20 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported as a recurring pathogenic variant in French Canadian, Sardinian, and Yemenite Jewish populations (PMID: 9792861, 17640379, 23621881, 29086229). This variant has been identified in 3/251142 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 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
(Dec 17, 2021)
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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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Ambry Genetics
Accession: SCV000186015.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.8537_8538delAG pathogenic mutation, located in coding exon 19 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 8537 to … (more)
The c.8537_8538delAG pathogenic mutation, located in coding exon 19 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 8537 to 8538, causing a translational frameshift with a predicted alternate stop codon (p.E2846Gfs*22). This mutation has been reported in multiple individuals and families with hereditary breast and ovarian cancer (HBOC) syndrome (Foretova L et al. Hum. Mutat. 2004 Apr;23(4):397-8; Palomba G et al. Cancer, 2005 Sep;104:1172-9; Machackova E et al. BMC Cancer, 2008 May;8:140; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7; Abd-Rabbo D et al. Cancer Prev. Res. 2012 May;5(5):765-77; Belanger MH et al. J Ovarian Res, 2015 Mar;8:1; El Ghorayeb N et al. Medicine (Baltimore), 2016 Sep;95:e4756; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Bernstein-Molho R et al. Breast Cancer Res Treat, 2018 02;167:697-702; Felix GES et al. Fam Cancer, 2018 10;17:471-483; Lowery MA et al. J Natl Cancer Inst, 2018 10;110:1067-1074; De Talhouet S et al. Sci Rep, 2020 04;10:7073; Dorling et al. N Engl J Med. 2021 02;384:428-439), and has also been reported in a family with a history of male breast and prostate cancer (Phelan CM et al. Nat. Genet. 1996 May;13(1):120-2). This mutation has also been reported in patients with pancreatic and gastric cancers (Halpern N et al. Onco Targets Ther, 2020 Nov;13:11637-11644; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration is known to be one of the more commonly occurring BRCA2 mutations in several different regions in Europe and North America (Tonin PN et al. Am J Hum Genet, 1998 Nov;63:1341-51; Manning AP et al. Hum Hered, 2001;52:116-20; Palomba G et al. BMC Cancer, 2007 Jul;7:132; Janavicius R. EPMA J. 2010 Sep;1(3):397-412). Of note, this alteration is also designated as 8535delAG, 8765delAG, c.8764_8765delAG and c.8537_8538del2 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Feb 17, 2020)
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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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GeneDx
Accession: SCV000210795.14
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
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; Not … (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; Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 8765delAG and 8765_8766delAG; This variant is associated with the following publications: (PMID: 23929434, 8673090, 16168118, 18489799, 21947752, 23302520, 23621881, 10422801, 15024741, 20694749, 26295337, 30014164, 28918466, 29086229, 29506128, 23199084, 25884701, 19656164, 26656232, 17640379, 25452441, 22798144, 21348412, 27836010, 27603373, 27160020, 25085752, 19619314, 15382066, 11512557, 9792861, 9634522, 21324516, 17591843, 16047344, 29560538, 22401979, 30720243, 30322717, 29625052) (less)
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Pathogenic
(Oct 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000327919.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Sep 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489211.2
First in ClinVar: Nov 05, 2016 Last updated: Dec 24, 2022 |
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Pathogenic
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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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: SCV002010306.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Pathogenic
(Jan 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296650.4
First in ClinVar: Oct 11, 2015 Last updated: Jan 06, 2024 |
Comment:
This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast cancer, ovarian cancer, … (more)
This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast cancer, ovarian cancer, and pancreatic cancer in the published literature (PMID: 30322717 (2018), 29625052 (2018), 29506128 (2018), 29086229 (2018), 21324516 (2011)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jan 29, 2024)
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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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Invitae
Accession: SCV000073563.16
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu2846Glyfs*22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu2846Glyfs*22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80359714, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8673090, 21324516, 22401979). It is commonly reported in individuals of French Canadian, Yemenite Jewish, and Northern Sardinian ancestry (PMID: 9634522, 9792861, 11512557, 15382066, 17640379, 19619314, 27603373). This variant is also known as 8765delAG. ClinVar contains an entry for this variant (Variation ID: 9328). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004846036.1
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 20 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 2 nucleotides in exon 20 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported as a recurring pathogenic variant in French Canadian, Sardinian, and Yemenite Jewish populations (PMID: 9792861, 17640379, 23621881, 29086229). This variant has been identified in 3/251142 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 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: 3
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Pathogenic
(Jul 24, 2014)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: unknown
Allele origin:
germline
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Pathway Genomics
Accession: SCV000189901.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
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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 2
Affected status: yes
Allele origin:
germline,
unknown
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000147396.2
First in ClinVar: Apr 01, 2014 Last updated: Oct 11, 2015 |
Observation 1:
Number of individuals with the variant: 10
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Native American
Observation 3:
Number of individuals with the variant: 2
Geographic origin: Western European
Observation 4:
Number of individuals with the variant: 11
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Observation 5:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian Non Hispanic
Observation 6:
Number of individuals with the variant: 14
Ethnicity/Population group: French Canadian
Observation 7:
Number of individuals with the variant: 23
Ethnicity/Population group: Western European
Observation 8:
Number of individuals with the variant: 7
Ethnicity/Population group: Western European, French Canadian
Observation 9:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Native American
Observation 10:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Native American, French Canadian
Observation 11:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Near Eastern
Observation 12:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Portuguese, French Canadian
Observation 13:
Number of individuals with the variant: 3
Observation 14:
Number of individuals with the variant: 1
Ethnicity/Population group: French Canadian
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Pathogenic
(Apr 22, 2013)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: not provided
Allele origin:
germline
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000054357.6
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
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Pathogenic
(Jul 01, 1998)
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no assertion criteria provided
Method: literature only
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BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030136.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 26, 2015 |
Comment on evidence:
Phelan et al. (1996) identified an 8765delAG mutation in the BRCA2 gene in 2 French Canadian patients whose families included 22 females with breast cancer … (more)
Phelan et al. (1996) identified an 8765delAG mutation in the BRCA2 gene in 2 French Canadian patients whose families included 22 females with breast cancer (BROVCA2; 612555) only, with mean age of diagnosis of 49.2 years. Lerer et al. (1998) found the same mutation in 3 Yemenite Jewish families with breast cancer; haplotype analysis indicated that the mutation was derived from a common ancestor. (less)
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Pathogenic
(Jan 31, 2014)
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no assertion criteria provided
Method: research
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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: SCV000587959.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
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Pathogenic
(May 11, 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: SCV000863619.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 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: SCV001451887.1
First in ClinVar: Dec 26, 2020 Last updated: Dec 26, 2020 |
Number of individuals with the variant: 3
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: SCV000592208.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The BRCA2 p.Glu2846GlyfsX22 variant was identified in 21 of 4958 proband chromosomes (frequency: 0.004) from individuals or families with breast and ovarian cancer (Phelan 1996, … (more)
The BRCA2 p.Glu2846GlyfsX22 variant was identified in 21 of 4958 proband chromosomes (frequency: 0.004) from individuals or families with breast and ovarian cancer (Phelan 1996, Zhang 2011, Machackova 2008, Pruss 2014, Seong M-W 2009, Tung 2016). The variant was also identified in the following databases: dbSNP (ID: rs80359714) as “With Pathogenic allele”, Clinvitae database (classified as pathogenic by ClinVar and Invitae), ARUP Laboratories BRCA Mutations Database (classification), the ClinVar database (classified as pathogenic by Invitae, Ambry genetics, GeneDx, LMMPHPM, QDNISJC, COGR, Pathway Genomics, BIC,OMIM, SCRP), COGR database (classified as pathogenic by a clinical laboratories MESHWCRI, LMM, CHEO, QUEENSU, NYG), the BIC database (76X with clinical importance), and UMD (16X with a causal classification). The variant was also identified in Exome Aggregation Consortium database (August 8, 2016) in the European population in 1 of 121324 chromosomes (freq. 0.000008). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The c.8537_8538del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2846 and leads to a premature stop codon 22 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
Number of individuals with the variant: 13
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
Prevalence of BRCA1/BRCA2 pathogenic variation in Chinese Han population. | Dong H | Journal of medical genetics | 2021 | PMID: 32467295 |
Clinical Characteristics and Prognosis of Gastric Cancer Patients with BRCA 1/2 Germline Mutations: Report of Ten Cases and a Literature Review. | Halpern N | OncoTargets and therapy | 2020 | PMID: 33235458 |
Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes. | De Talhouet S | Scientific reports | 2020 | PMID: 32341426 |
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 pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. | Lowery MA | Journal of the National Cancer Institute | 2018 | PMID: 29506128 |
The yield of targeted genotyping for the recurring mutations in BRCA1/2 in Israel. | Bernstein-Molho R | Breast cancer research and treatment | 2018 | PMID: 29086229 |
Mutations in context: implications of BRCA testing in diverse populations. | Felix GES | Familial cancer | 2018 | PMID: 28918466 |
First case report of an adrenocortical carcinoma caused by a BRCA2 mutation. | El Ghorayeb N | Medicine | 2016 | PMID: 27603373 |
A targeted analysis identifies a high frequency of BRCA1 and BRCA2 mutation carriers in women with ovarian cancer from a founder population. | Belanger MH | Journal of ovarian research | 2015 | PMID: 25884701 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Screening for BRCA1 and BRCA2 mutations among French-Canadian breast cancer cases attending an outpatient clinic in Montreal. | Ghadirian P | Clinical genetics | 2014 | PMID: 23621881 |
Allelic transcripts dosage effect in morphologically normal ovarian cells from heterozygous carriers of a BRCA1/2 French Canadian founder mutation. | Abd-Rabbo D | Cancer prevention research (Philadelphia, Pa.) | 2012 | PMID: 22401979 |
Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. | Zhang S | Gynecologic oncology | 2011 | PMID: 21324516 |
Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. | Janavičius R | The EPMA journal | 2010 | PMID: 23199084 |
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 |
A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population. | Palomba G | BMC cancer | 2009 | PMID: 19619314 |
Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. | Machackova E | BMC cancer | 2008 | PMID: 18489799 |
Origin and distribution of the BRCA2-8765delAG mutation in breast cancer. | Palomba G | BMC cancer | 2007 | PMID: 17640379 |
Founder mutations in BRCA1 and BRCA2 genes. | Ferla R | Annals of oncology : official journal of the European Society for Medical Oncology | 2007 | PMID: 17591843 |
Spectrum and prevalence of BRCA1 and BRCA2 germline mutations in Sardinian patients with breast carcinoma through hospital-based screening. | Palomba G | Cancer | 2005 | PMID: 16047344 |
Significant proportion of breast and/or ovarian cancer families of French Canadian descent harbor 1 of 5 BRCA1 and BRCA2 mutations. | Oros KK | International journal of cancer | 2004 | PMID: 15382066 |
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 |
Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families. | Manning AP | Human heredity | 2001 | PMID: 11512557 |
Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families. | Tonin PN | American journal of human genetics | 1998 | PMID: 9792861 |
The 8765delAG mutation in BRCA2 is common among Jews of Yemenite extraction. | Lerer I | American journal of human genetics | 1998 | PMID: 9634522 |
Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. | Phelan CM | Nature genetics | 1996 | PMID: 8673090 |
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Text-mined citations for rs80359714 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.