ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.8941G>A (p.Glu2981Lys)
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(7); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.8941G>A (p.Glu2981Lys)
Variation ID: 41571 Accession: VCV000041571.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32379503 (GRCh38) [ NCBI UCSC ] 13: 32953640 (GRCh37) [ NCBI UCSC ] 13: 31851640 (NCBI36) [ 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 12, 2013 Oct 20, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.8941G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Glu2981Lys missense NC_000013.11:g.32379503G>A NC_000013.10:g.32953640G>A NG_012772.3:g.69024G>A LRG_293:g.69024G>A LRG_293t1:c.8941G>A LRG_293p1:p.Glu2981Lys - Protein change
- E2981K
- Other names
- p.E2981K:GAA>AAA
- Canonical SPDI
- NC_000013.11:32379502:G:A
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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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
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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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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jan 1, 2024 | RCV000034470.23 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 26, 2023 | RCV000130691.24 | |
Likely benign (1) |
criteria provided, single submitter
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Oct 17, 2023 | RCV001364532.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 15, 2023 | RCV003473252.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 13, 2023 | RCV003996169.2 |
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
(Sep 15, 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: SCV004211948.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely benign
(Oct 17, 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: SCV001560685.4
First in ClinVar: Apr 13, 2021 Last updated: Feb 28, 2024 |
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Uncertain significance
(Jul 05, 2018)
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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: SCV000210539.13
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
This variant is denoted BRCA2 c.8941G>A at the cDNA level, p.Glu2981Lys (E2981K) at the protein level, and results in the change of a Glutamic Acid … (more)
This variant is denoted BRCA2 c.8941G>A at the cDNA level, p.Glu2981Lys (E2981K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 9169G>A. This variant has been observed in individuals diagnosed with early-onset and/or familial breast cancer, ovarian cancer, and early-onset or familial prostate cancer (Hansen 2011, Maier 2014, Caminsky 2016). BRCA2 Glu2981Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA Binding Domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Glu2981Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Dec 20, 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
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Sema4, Sema4
Accession: SCV002531988.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA2 c.8941G>A (p.Glu2981Lys) variant has been reported in heterozygosity in at least 3 individuals with breast and prostate cancer (PMID: 21318380, 25111659). It was … (more)
The BRCA2 c.8941G>A (p.Glu2981Lys) variant has been reported in heterozygosity in at least 3 individuals with breast and prostate cancer (PMID: 21318380, 25111659). It was observed in 3/16014 chromosomes of the African/African American (AFR) subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 41571). In silico predictions of the variant's effect on protein function are inconclusive. A homologous recombination deficiency repair study demonstrated the normal function of the protein (PMID: 29884841). The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Nov 10, 2017)
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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: SCV000887948.3
First in ClinVar: Apr 12, 2013 Last updated: Dec 31, 2022 |
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Uncertain significance
(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: SCV002010297.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Likely benign
(Dec 06, 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: SCV000185578.8
First in ClinVar: Aug 06, 2014 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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Likely benign
(Jan 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004698594.8
First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024 |
Comment:
BRCA2: BP1, BP4, BS3:Supporting
Number of individuals with the variant: 1
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Uncertain significance
(Jan 26, 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: SCV000689159.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with lysine at codon 2981 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant … (more)
This missense variant replaces glutamic acid with lysine at codon 2981 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant does not impact homology-directed DNA repair activity (PMID: 29884841, 35736817). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 21318380, 28480178, 35535289), and prostate cancer (PMID: 25111659). One of the individuals affected with ovarian cancer also carried a pathogenic variant in the BRCA1 gene, which could explain the observed phenotype (PMID: 35535289). This variant has been identified in 1/242750 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Dec 13, 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: SCV004846097.1
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 missense variant replaces glutamic acid with lysine at codon 2981 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant … (more)
This missense variant replaces glutamic acid with lysine at codon 2981 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant does not impact homology-directed DNA repair activity (PMID: 29884841, 35736817). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 21318380, 28480178, 35535289), and prostate cancer (PMID: 25111659). One of the individuals affected with ovarian cancer also carried a pathogenic variant in the BRCA1 gene, which could explain the observed phenotype (PMID: 35535289). This variant has been identified in 1/242750 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 6
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variant of unknown significance
(Jul 13, 2012)
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no assertion criteria provided
Method: research
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not provided
Affected status: no
Allele origin:
germline
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043236.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Uncertain significance.
Number of individuals with the variant: 1
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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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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Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay. | Hu C | Clinical cancer research : an official journal of the American Association for Cancer Research | 2022 | PMID: 35736817 |
Fallopian Tube Originating Ovarian Cancer in a 53-Year-Old Postmenopausal Female With Hereditary Breast Cancer (BRCA) Genes: A Case Study. | Garrick I | Cureus | 2022 | PMID: 35535289 |
Operationalization of Next-Generation Sequencing and Decision Support for Precision Oncology. | Zeng J | JCO clinical cancer informatics | 2019 | PMID: 31550176 |
Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. | Hart SN | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29884841 |
Next-generation sequencing of BRCA1/2 in breast cancer patients: potential effects on clinical decision-making using rapid, high-accuracy genetic results. | Park HS | Annals of surgical treatment and research | 2017 | PMID: 28480178 |
Subgroups of familial and aggressive prostate cancer with considerable frequencies of BRCA2 mutations. | Maier C | The Prostate | 2014 | PMID: 25111659 |
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 |
Screening of 1331 Danish breast and/or ovarian cancer families identified 40 novel BRCA1 and BRCA2 mutations. | Hansen TV | Familial cancer | 2011 | PMID: 21318380 |
Text-mined citations for rs139052578 ...
HelpRecord last updated Oct 20, 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.