Submissions for variant NM_000059.4(BRCA2):c.2837A>T (p.Asp946Val)

dbSNP: rs55972907

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226769	SCV000283197	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with valine at codon 946 of the BRCA2 protein (p.Asp946Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998503	SCV000600526	uncertain significance	not provided	2024-10-31	criteria provided, single submitter	clinical testing	The BRCA2 c.2837A>T (p.Asp946Val) variant has been reported in the published literature as having an inconclusive effect on protein function in a functional study (PMID: 36471068 (2022)), and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). This variant 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.
Ambry Genetics	RCV002433944	SCV002750463	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-17	criteria provided, single submitter	clinical testing	The p.D946V variant (also known as c.2837A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 2837. The aspartic acid at codon 946 is replaced by valine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002433944	SCV003850175	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	RCV003998698	SCV004832002	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 946 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). A cell population-based knock-in assay functional study showed that this variant does not impact cell viability or response to PARP inhibitors (PMID: 36471068). To our knowledge, this variant has not been reported in individuals affected with BRCA2-related disorders in the literature. 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.