Submissions for variant NM_000059.4(BRCA2):c.9433G>A (p.Val3145Met)

dbSNP: rs587776476

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217472	SCV000275245	likely benign	Hereditary cancer-predisposing syndrome	2024-01-01	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227102	SCV000283367	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-21	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 3145 of the BRCA2 protein (p.Val3145Met). This variant is present in population databases (rs587776476, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 156180). 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.
GeneDx	RCV000486980	SCV000565721	uncertain significance	not provided	2022-06-16	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 9661G>A; This variant is associated with the following publications: (PMID: 12228710)
Counsyl	RCV000144197	SCV000785310	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000217472	SCV001355352	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 3145 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature, but has been reported in 2 healthy controls (PMID: 33471991). This variant has been identified in 1/251342 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.
Sema4, Sema4	RCV000217472	SCV002532033	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-01	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000144197	SCV000189270	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-05-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532627	SCV004116104	uncertain significance	BRCA2-related disorder	2024-07-17	no assertion criteria provided	clinical testing	The BRCA2 c.9433G>A variant is predicted to result in the amino acid substitution p.Val3145Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has interpretations of likely benign (1) and uncertain (7) (https://preview.ncbi.nlm.nih.gov/clinvar/variation/156180/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.