ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.4376A>G (p.Asn1459Ser)
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.
Uncertain significance(5); Likely benign(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.4376A>G (p.Asn1459Ser)
Variation ID: 37898 Accession: VCV000037898.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32338731 (GRCh38) [ NCBI UCSC ] 13: 32912868 (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 1, 2014 May 1, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.4376A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Asn1459Ser missense NC_000013.11:g.32338731A>G NC_000013.10:g.32912868A>G NG_012772.3:g.28252A>G LRG_293:g.28252A>G LRG_293t1:c.4376A>G LRG_293p1:p.Asn1459Ser U43746.1:n.4604A>G - Protein change
- N1459S
- Other names
- 4604A>G
- Canonical SPDI
- NC_000013.11:32338730:A:G
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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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0.00020 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
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 |
18955 | 19114 |
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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Aug 15, 2023 | RCV000031479.16 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 21, 2024 | RCV000044400.21 | |
Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Mar 23, 2023 | RCV000166927.23 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 1, 2015 | RCV000240790.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 6, 2023 | RCV000481899.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 27, 2017 | RCV000677824.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 27, 2017 | RCV000677823.9 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV002250488.9 | |
Likely benign (1) |
criteria provided, single submitter
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May 25, 2023 | RCV003234931.8 |
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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Uncertain significance
(Dec 10, 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:
unknown
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Counsyl
Accession: SCV000487988.2
First in ClinVar: Sep 27, 2014 Last updated: Dec 24, 2022 |
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Likely benign
(Jan 21, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000072413.12
First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024 |
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Uncertain significance
(Nov 01, 2015)
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criteria provided, single submitter
Method: research
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Breast neoplasm
Affected status: yes
Allele origin:
germline
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Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University
Additional submitter:
Asia and Emerging Markets iMed, AstraZeneca
Accession: SCV000265940.1
First in ClinVar: Sep 14, 2016 Last updated: Sep 14, 2016 |
Number of individuals with the variant: 1
Geographic origin: China
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Likely benign
(Mar 23, 2023)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV003850463.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Comment:
BRCA2 exon 11 coldspot. Reclassification based on statistical prior probability.
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Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
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Likely benign
(Sep 03, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000911008.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
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Likely Benign
(Aug 15, 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: SCV004845676.1
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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Number of individuals with the variant: 2
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Uncertain significance
(Feb 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Ovarian cancer
Affected status: yes
Allele origin:
germline
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3DMed Clinical Laboratory Inc
Accession: SCV000803984.1
First in ClinVar: Aug 26, 2018 Last updated: Aug 26, 2018 |
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Uncertain significance
(Feb 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Invasive Lobular Breast Carcinoma
Affected status: yes
Allele origin:
germline
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3DMed Clinical Laboratory Inc
Accession: SCV000803983.1
First in ClinVar: Aug 26, 2018 Last updated: Aug 26, 2018 |
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Uncertain significance
(Feb 06, 2023)
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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: SCV000568107.7
First in ClinVar: Apr 29, 2017 Last updated: Mar 04, 2023 |
Comment:
Observed in individuals with breast or ovarian cancer (Suter 2004, Chao 2016, Zhong 2016, Lai 2017, Li 2017, Chen 2020); In silico analysis supports that … (more)
Observed in individuals with breast or ovarian cancer (Suter 2004, Chao 2016, Zhong 2016, Lai 2017, Li 2017, Chen 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 4604A>G; This variant is associated with the following publications: (PMID: 14973102, 28664449, 31131967, 27257965, 28222693, 27907908, 27157322, 31867841, 30702160, 31825140, 32467295, 29884841, 32377563) (less)
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Likely benign
(May 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003933861.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: BRCA2 c.4376A>G (p.Asn1459Ser) results in a conservative amino acid change located in the BRCA2 repeat region (IPR002093), located between repeat 3 and 4 … (more)
Variant summary: BRCA2 c.4376A>G (p.Asn1459Ser) results in a conservative amino acid change located in the BRCA2 repeat region (IPR002093), located between repeat 3 and 4 of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 276508 control chromosomes, exclusively reported within the East Asian subpopulation at a frequency of 0.0006 (in the gnomAD v2.1 dataset). This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (0.00075), allowing no clear conclusions about variant significance. The variant, c.4376A>G, has been reported in the literature in individuals of East Asian origin affected with breast- or ovarian cancer (Lai_2017, Bhaskaran_2019), but was also found in several unaffected East Asian controls (Lai_2017, Momozawa_2018, Dong_2021). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 7/60466 cases, but was also found in 9/53461 controls (Dorling_2021, reported through LOVD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a large scale study utilizing multifactorial probability model for quantitative analysis of BRCA1 and BRCA2 variants predicted this variant to be likely benign (Parsons_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31131967, 28222693, 30287823, 30702160, 32467295, 33471991). Eight submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=5) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Jul 01, 2019)
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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: SCV000217746.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Dec 02, 2009)
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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: SCV000054084.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
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Uncertain significance
(Sep 18, 2010)
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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
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000146415.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
Ethnicity/Population group: Chinese
Geographic origin: Malaysia
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Uncertain significance
(-)
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no assertion criteria provided
Method: literature only
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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Center for Precision Medicine, Meizhou People's Hospital
Accession: SCV002520790.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
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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 |
Prevalence of BRCA1/BRCA2 pathogenic variation in Chinese Han population. | Dong H | Journal of medical genetics | 2021 | PMID: 32467295 |
Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". | Dines JN | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31911673 |
Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. | Parsons MT | Human mutation | 2019 | PMID: 31131967 |
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 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Analysis of BRCA1/2 mutation spectrum and prevalence in unselected Chinese breast cancer patients by next-generation sequencing. | Li G | Journal of cancer research and clinical oncology | 2017 | PMID: 28664449 |
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. | Nykamp K | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28492532 |
Characterization of BRCA1 and BRCA2 variants in multi-ethnic Asian cohort from a Malaysian case-control study. | Lai KN | BMC cancer | 2017 | PMID: 28222693 |
Prevalence and Prognostic Role of BRCA1/2 Variants in Unselected Chinese Breast Cancer Patients. | Zhong X | PloS one | 2016 | PMID: 27257965 |
BRCA1 and BRCA2 mutations in women from Shanghai China. | Suter NM | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2004 | PMID: 14973102 |
The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
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Text-mined citations for rs117187202 ...
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.