Submissions for variant NM_000059.4(BRCA2):c.8941G>A (p.Glu2981Lys)

dbSNP: rs139052578

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130691	SCV000185578	likely benign	Hereditary cancer-predisposing syndrome	2019-12-06	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000034470	SCV000210539	uncertain significance	not provided	2018-07-05	criteria provided, single submitter	clinical testing	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.
Color Diagnostics, LLC DBA Color Health	RCV000130691	SCV000689159	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-26	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034470	SCV000887948	uncertain significance	not provided	2017-11-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001364532	SCV001560685	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-17	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034470	SCV002010297	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130691	SCV002531988	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	curation
Baylor Genetics	RCV003473252	SCV004211948	uncertain significance	Familial cancer of breast	2023-09-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034470	SCV004698594	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP4, BS3:Supporting
All of Us Research Program, National Institutes of Health	RCV003996169	SCV004846097	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing	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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034470	SCV000043236	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.