Submissions for variant NM_000059.4(BRCA2):c.7931A>G (p.Asn2644Ser)

gnomAD frequency: 0.00001  dbSNP: rs80359020

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162644	SCV000213081	likely benign	Hereditary cancer-predisposing syndrome	2022-01-05	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.
Genetic Services Laboratory, University of Chicago	RCV000501144	SCV000593756	uncertain significance	not specified	2016-01-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000077417	SCV000784833	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-12-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162644	SCV000906944	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 2644 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 an individual affected with breast cancer (PMID: 31780696) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0246 and 0.6533, respectively (PMID: 31131967). This variant has been identified in 1/251308 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501144	SCV001363207	uncertain significance	not specified	2024-03-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7931A>G (p.Asn2644Ser) results in a conservative amino acid change located in the BRCA2 helical domain superfamily (IPR036315) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. Also a bioinformatics method that integrates information from protein sequence, structure, and sequence conservation into a likelihood ratio predicted variant to be neutral (Karchin_2008). The variant allele was found at a frequency of 4e-06 in 251308 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7931A>G has been reported in the literature in at-least one individual affected with breast cancer (Dutil_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31780696, 19043619). ClinVar contains an entry for this variant (Variation ID: 52439). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001325093	SCV001516070	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2644 of the BRCA2 protein (p.Asn2644Ser). This variant is present in population databases (rs80359020, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 31780696). ClinVar contains an entry for this variant (Variation ID: 52439). 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.
GeneDx	RCV003159092	SCV003852934	uncertain significance	not provided	2023-11-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Identified in a patient with breast cancer (PMID: 31780696); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8159A>G; This variant is associated with the following publications: (PMID: 19043619, 31131967, 31911673, 29884841, 32377563, 31853058, 12228710, 31780696)
All of Us Research Program, National Institutes of Health	RCV000077417	SCV004845573	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 2644 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 an individual affected with breast cancer (PMID: 31780696) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0246 and 0.6533, respectively (PMID: 31131967). This variant has been identified in 1/251308 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.
Baylor Genetics	RCV004566842	SCV005059051	uncertain significance	Familial cancer of breast	2024-02-17	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001325093	SCV005415579	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-16	criteria provided, single submitter	clinical testing	The missense variant NM_000059.4(BRCA2):c.7931A>G (p.Asn2644Ser) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asn2644Ser variant is observed in 1/113,608 (0.0009%) alleles from individuals of gnomAD Non Finnish European background in gnomAD. The p.Asn2644Ser variant is novel (not in any individuals) in 1kG. There is a small physicochemical difference between asparagine and serine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene BRCA2 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.00. The p.Asn2644Ser variant is not predicted to introduce a novel splice site by any splice site algorithm. The serine residue at codon 2644 of BRCA2 is present in Guinea pig and 8 other mammalian species. The nucleotide c.7931 in BRCA2 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003159092	SCV005625298	uncertain significance	not provided	2024-03-13	criteria provided, single submitter	clinical testing	The BRCA2 c.7931A>G (p.Asn2644Ser) variant has been reported in an individual with breast cancer (PMID: 31780696 (2019)). Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive (PMID: 35190686 (2022)). The frequency of this variant in the general population, 0.0000088 (1/113608 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sharing Clinical Reports Project (SCRP)	RCV000077417	SCV000109215	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2007-04-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077417	SCV000147219	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing