Submissions for variant NM_000059.4(BRCA2):c.8036A>G (p.Asp2679Gly)

gnomAD frequency: 0.00004  dbSNP: rs80359041

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045397	SCV000073410	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2679 of the BRCA2 protein (p.Asp2679Gly). This variant is present in population databases (rs80359041, gnomAD 0.02%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 33008098). ClinVar contains an entry for this variant (Variation ID: 52481). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 23108138, 29884841, 35736817). 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.
Ambry Genetics	RCV000131797	SCV000186848	likely benign	Hereditary cancer-predisposing syndrome	2020-06-04	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.
Counsyl	RCV000113859	SCV000489186	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-08-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000484310	SCV000567541	likely benign	not specified	2018-02-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Diagnostics, LLC DBA Color Health	RCV000131797	SCV000683938	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 2679 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant does not impact homology-directed DNA repair activity (PMID: 23108138, 29884841, 33609447). This variant has been reported in two individuals affected with breast or ovarian cancer and in an unaffected individual (PMID: 33008098, 33471991; Leiden Open Variation Database DB-ID BRCA2_000266). This variant has been identified in 7/282620 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	RCV000759667	SCV000889149	uncertain significance	not provided	2024-09-04	criteria provided, single submitter	clinical testing	The BRCA2 c.8036A>G (p.Asp2679Gly) variant has been reported in the published literature in individuals with breast and/or ovarian cancer, as well as a reportedly healthy individual (PMIDs: 33008098 (2020) and 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). In vitro functional studies have shown that this variant does not substantially affect BRCA2 protein function in homology-directed DNA repair (HDR) assays (PMIDs: 23108138 (2013), 29884841 (2019), and 35736817 (2022)) The frequency of this variant in the general population, 0.00017 (6/35420 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000484310	SCV000916951	likely benign	not specified	2024-01-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8036A>G (p.Asp2679Gly) results in a non-conservative amino acid change located in the DNA binding domain (Guidugli_2012) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251214 control chromosomes, predominantly at a frequency of 0.00014 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8036A>G has been reported in the literature as a VUS in individuals affected with breast cancer or ovarian cancer (e.g. Guidugli_2012, Peixoto_2020) . These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In vitro functional studies reported that this variant results in activity comparable to wild type in homology-directed DNA repair (HDR) assays (e.g. Guidugli_2012, Guidugli_2018, Richardson_2021), showing no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 24817641, 23108138, 24323938, 29394989, 29884841, 35736817, 19043619, 32850417, 33609447). ClinVar contains an entry for this variant (Variation ID: 52481). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000113859	SCV001139204	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131797	SCV002531907	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-27	criteria provided, single submitter	curation
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000113859	SCV003807428	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-04-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderated
All of Us Research Program, National Institutes of Health	RCV004803903	SCV004845592	uncertain significance	BRCA2-related cancer predisposition	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 2679 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant does not impact homology-directed DNA repair activity (PMID: 23108138, 29884841, 33609447). This variant has been reported in two individuals affected with breast or ovarian cancer and in an unaffected individual (PMID: 33008098, 33471991; Leiden Open Variation Database DB-ID BRCA2_000266). This variant has been identified in 7/282620 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113859	SCV000147255	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2001-10-29	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732626	SCV005345165	uncertain significance	BRCA2-related disorder	2024-03-06	no assertion criteria provided	clinical testing	The BRCA2 c.8036A>G variant is predicted to result in the amino acid substitution p.Asp2679Gly. This variant has been reported in two individuals in the Breast Cancer Information Core database (Szabo et al. 2000. PubMed ID: 10923033). Using functional and computational approaches this variant was reported to be benign (Guidugli et al. 2018. PubMed ID: 29394989). In vitro experimental studies indicate this variant does not impact homology-directed DNA repair activity (Guidugli et al. 2012. PubMed ID: 23108138;). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52481/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.