Submissions for variant NM_000059.4(BRCA2):c.6029T>G (p.Val2010Gly)

gnomAD frequency: 0.00002  dbSNP: rs80358839

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129746	SCV000184552	benign	Hereditary cancer-predisposing syndrome	2024-07-25	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000212246	SCV000210380	uncertain significance	not provided	2020-02-04	criteria provided, single submitter	clinical testing	Observed in individuals with breast and other cancers (Inoue 1997, Kurian 2008, Haffty 2009, Lu 2015, Nakamura 2015, Yoon 2017, Momozawa 2018, So 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.6257T>G; This variant is associated with the following publications: (PMID: 29338689, 18779604, 30415210, 30287823, 9133456, 24249303, 19491284, 26689913, 27658390, 30725392, 29215753, 31131967, 31822803, 29176636)
Counsyl	RCV000077367	SCV000488374	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000709322	SCV000838829	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212246	SCV001133848	uncertain significance	not provided	2019-04-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129746	SCV001350864	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 2010 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals with a personal or family history of breast or ovarian cancer and in two individuals affected with esophageal cancer (PMID: 9133456,18779604, 24249303, 27658390, 29176636, 29215753, 31396961, 35681111). This variant has also been detected in breast, pancreatic, and prostate cancer case-control studies in which disease association could not be established (PMID: 30287823, 31214711, 32980694, 33471991; Leiden Open Variation Database DB-ID BRCA2_002250). This variant has been identified in 5/250814 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000709322	SCV001562992	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2010 of the BRCA2 protein (p.Val2010Gly). This variant is present in population databases (rs80358839, gnomAD 0.03%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer, stomach adenocarcinoma (PMID: 18779604, 19491284, 26689913, 27124784, 27658390, 29176636, 29215753, 30287823, 31907386). ClinVar contains an entry for this variant (Variation ID: 51991). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129746	SCV003850872	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000077367	SCV004846684	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 2010 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer or prostate cancer, and has been reported in several unaffected individuals (PMID: 18779604, 24249303, 27658390, 29215753, 31214711, 32980694). In 2 large breast cancer case-control studies conducted in Japan and by the BRIDGES consortium, this variant was reported in 5/7051 female cases and 9/11241 female controls (OR=0.885632780741425 (0.2-2.9)) (PMID: 30287823), and in 2/60466 cases and 4/53461 controls (OR=0.442 (95%CI 0.081 to 2.414); p-value=0.429) (PMID: 33471991), respectively. This variant has been identified in 5/250814 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.
Sharing Clinical Reports Project (SCRP)	RCV000077367	SCV000109164	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-08-24	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077367	SCV000146753	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing