Submissions for variant NM_000059.4(BRCA2):c.928T>G (p.Leu310Val)

gnomAD frequency: 0.00001  dbSNP: rs778907270

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219199	SCV000274916	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-23	criteria provided, single submitter	clinical testing	The p.L310V variant (also known as c.928T>G), located in coding exon 9 of the BRCA2 gene, results from a T to G substitution at nucleotide position 928. The leucine at codon 310 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460087	SCV000549671	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 310 of the BRCA2 protein (p.Leu310Val). This variant is present in population databases (rs778907270, gnomAD 0.01%). 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: 231157). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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	RCV000219199	SCV000905818	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 310 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 not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 2/234070 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	RCV000985622	SCV001133974	uncertain significance	not provided	2024-09-25	criteria provided, single submitter	clinical testing	The BRCA2 c.928T>G (p.Leu310Val) variant has been reported in the published literature in individuals with a personal and/or family history of cancer (PMID: 31853058 (2020)), and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.0000085 (2/234070 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.
GeneDx	RCV000985622	SCV002007318	uncertain significance	not provided	2019-10-08	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 1156T>G
University of Washington Department of Laboratory Medicine, University of Washington	RCV000219199	SCV003848142	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).
Myriad Genetics, Inc.	RCV003335250	SCV004043187	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health	RCV004804885	SCV004846838	uncertain significance	BRCA2-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 310 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 not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 2/234070 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.