Submissions for variant NM_000059.4(BRCA2):c.2380A>G (p.Met794Val)

gnomAD frequency: 0.00001  dbSNP: rs786203635

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167035	SCV000217859	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	clinical testing	The p.M794V variant (also known as c.2380A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 2380. The methionine at codon 794 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000505884	SCV000600507	uncertain significance	not specified	2016-11-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688301	SCV000815906	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 794 of the BRCA2 protein (p.Met794Val). This variant is present in population databases (rs786203635, gnomAD 0.006%). 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: 187316). 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.
Color Diagnostics, LLC DBA Color Health	RCV000167035	SCV000906853	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505884	SCV001623393	uncertain significance	not specified	2021-04-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2380A>G (p.Met794Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2380A>G in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000167035	SCV003848268	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	RCV004804771	SCV005424326	uncertain significance	BRCA2-related cancer predisposition	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 794 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 2/250466 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.