Submissions for variant NM_000059.4(BRCA2):c.9637A>G (p.Asn3213Asp)

dbSNP: rs80359235

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045871	SCV000073884	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 3213 of the BRCA2 protein (p.Asn3213Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52877). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Ambry Genetics	RCV000129983	SCV000184807	likely benign	Hereditary cancer-predisposing syndrome	2018-09-28	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	RCV000114138	SCV000784990	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-03-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778689	SCV002015150	uncertain significance	not specified	2021-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001852967	SCV002107190	uncertain significance	not provided	2022-07-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 9865A>G; This variant is associated with the following publications: (PMID: 10923033, 27535533, 31131967)
All of Us Research Program, National Institutes of Health	RCV004803945	SCV004846210	uncertain significance	BRCA2-related cancer predisposition	2024-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 3213 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 a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.076 and 0.733, respectively (PMID: 31131967). This variant has not been identified 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	RCV001852967	SCV005625357	uncertain significance	not provided	2023-11-22	criteria provided, single submitter	clinical testing	The BRCA2 c.9637A>G (p.Asn3213Asp) variant has not been reported in individuals with BRCA2-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114138	SCV000147682	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing