ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.3668_3671dup (p.Cys1225fs)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007294.4(BRCA1):c.3668_3671dup (p.Cys1225fs)
Variation ID: 54960 Accession: VCV000054960.31
- Type and length
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Duplication, 4 bp
- Location
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Cytogenetic: 17q21.31 17: 43091859-43091860 (GRCh38) [ NCBI UCSC ] 17: 41243876-41243877 (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 Apr 4, 2014 Sep 16, 2024 Apr 22, 2016 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- C1178fs, C1225fs, C1114fs, C1158fs, C1177fs, C1183fs, C1057fs, C1157fs, C1198fs, C357fs, C1137fs, C1199fs, C1224fs, C929fs, C1097fs, C1098fs, C1113fs, C1136fs, C1154fs, C1155fs, C1184fs, C1222fs
- Other names
- 3790ins4
- 3790_3791insTTCC
- Canonical SPDI
- NC_000017.11:43091859:GGAAG:GGAAGGAAG
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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
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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
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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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BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13037 | 14843 | |
LOC126862571 | - | - | - | GRCh38 | - | 1651 |
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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Nov 19, 2023 | RCV000048279.24 | |
Pathogenic (5) |
reviewed by expert panel
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Apr 22, 2016 | RCV000112152.16 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 18, 2023 | RCV000129597.18 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 13, 2024 | RCV000159921.21 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV000735459.9 |
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
(Apr 22, 2016)
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reviewed by expert panel
Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000282313.1
First in ClinVar: Jun 24, 2016 Last updated: Jun 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
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Pathogenic
(Mar 16, 2023)
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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: SCV003923032.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: BRCA1 c.3668_3671dupTTCC (p.Cys1225SerfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: BRCA1 c.3668_3671dupTTCC (p.Cys1225SerfsX10) 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 was absent in 251296 control chromosomes. c.3668_3671dupTTCC has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Alsop_2012, Scottish-NorthernIrishConsortium_2003, Claus_2005, Evans_2022). These data indicate that the variant is likely to be associated with disease. Seven submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 05, 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: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004215038.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Apr 18, 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: SCV000688446.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant inserts 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known … (more)
This variant inserts 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.3671_3672insTTCC and 3790ins4. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least five individuals affected with breast and ovarian cancer (PMID: 12698193, 15728167, 22711857, 26718727; Color internal data). This variant has not been identified 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
(Aug 24, 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: SCV000184381.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.3668_3671dupTTCC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of TTCC at nucleotide position 3668, causing a … (more)
The c.3668_3671dupTTCC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of TTCC at nucleotide position 3668, causing a translational frameshift with a predicted alternate stop codon (p.C1225Sfs*10). This mutation has been reported in multiple individuals with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Scottish/Northern Irish BRCA1/BRCA2 Consortium. Br. J. Cancer, 2003 Apr;88:1256-62; Claus EB et al. JAMA, 2005 Feb;293:964-9; Alsop K et al. J Clin Oncol, 2012 Jul;30:2654-63; Bernards SS et al. Gynecol. Oncol., 2016 Feb;140:221-5; Susswein LR et al. Genet Med, 2016 08;18:823-32; Arvai KJ et al. Hered Cancer Clin Pract, 2019 Jul;17:19). Of note, this alteration is also designated as 3790ins4 and 3790insTTCC in the 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
(Oct 02, 2015)
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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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Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000325718.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Jan 09, 2023)
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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: SCV000600340.3
First in ClinVar: Sep 28, 2017 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, 0.0000066 (1/152238 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in several individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 12698193 (2003), 15728167 (2005), 22711857 (2012), 26718727 (2016), 33758026 (2022)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Nov 19, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000076292.10
First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys1225Serfs*10) 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.Cys1225Serfs*10) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 12698193, 15728167, 22711857, 26718727). This variant is also known as 3790ins4. ClinVar contains an entry for this variant (Variation ID: 54960). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 09, 2023)
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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: SCV004817768.1
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 inserts 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known … (more)
This variant inserts 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.3671_3672insTTCC and 3790ins4. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least five individuals affected with breast and ovarian cancer (PMID: 15728167, 22711857, 26718727; Color internal data) and in suspected hereditary breast and ovarian cancer families (PMID: 12698193). This variant has not been identified 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: 2
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Pathogenic
(Aug 13, 2024)
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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: SCV000210045.12
First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024 |
Comment:
Observed in individuals with personal or family history consistent with hereditary breast and ovarian cancer (PMID: 15728167, 22711857, 26718727); Frameshift variant predicted to result in … (more)
Observed in individuals with personal or family history consistent with hereditary breast and ovarian cancer (PMID: 15728167, 22711857, 26718727); 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 significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3671_3672insTTCC, 3790insTTCC, and 3790ins4; This variant is associated with the following publications: (PMID: 12112659, 12698193, 22711857, 15728167, 26681312, 23242139, 26315209, 21295272, 26718727, 33758026) (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
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Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000144833.1
First in ClinVar: Apr 04, 2014 Last updated: Apr 04, 2014 |
Observation 1:
Number of individuals with the variant: 8
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Observation 4:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: English
Observation 5:
Number of individuals with the variant: 3
Ethnicity/Population group: Western European
Observation 6:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Latin American, Caribbe
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Pathogenic
(-)
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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: SCV000863596.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
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: SCV000591462.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Number of individuals with the variant: 2
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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: SCV000587331.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
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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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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 |
Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients. | Gao X | Human mutation | 2020 | PMID: 31825140 |
Age-adjusted association of homologous recombination genes with ovarian cancer using clinical exomes as controls. | Arvai KJ | Hereditary cancer in clinical practice | 2019 | PMID: 31341520 |
Incidence of BRCA1 somatic mutations and response to neoadjuvant chemotherapy in Chinese women with triple-negative breast cancer. | Li M | Gene | 2016 | PMID: 26956035 |
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 |
The validation and clinical implementation of BRCAplus: a comprehensive high-risk breast cancer diagnostic assay. | Chong HK | PloS one | 2014 | PMID: 24830819 |
Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. | Ruark E | Nature | 2013 | PMID: 23242139 |
BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. | Alsop K | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22711857 |
A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes. | Hondow HL | BMC cancer | 2011 | PMID: 21702907 |
Prevalence and predictors of loss of wild type BRCA1 in estrogen receptor positive and negative BRCA1-associated breast cancers. | Tung N | Breast cancer research : BCR | 2010 | PMID: 21080930 |
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 |
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. | Judkins T | Cancer research | 2005 | PMID: 16267036 |
Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ. | Claus EB | JAMA | 2005 | PMID: 15728167 |
BRCA1 and BRCA2 mutations in Scotland and Northern Ireland. | Scottish/Northern Irish BRCAI/BRCA2 Consortium | British journal of cancer | 2003 | PMID: 12698193 |
Comparison of DNA- and RNA-based methods for detection of truncating BRCA1 mutations. | Andrulis IL | Human mutation | 2002 | PMID: 12112659 |
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Text-mined citations for rs80357797 ...
HelpRecord last updated Oct 13, 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.