Submissions for variant NM_000059.4(BRCA2):c.1159G>T (p.Val387Phe)

gnomAD frequency: 0.00001  dbSNP: rs869320791

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Michigan Medical Genetics Laboratories, University of Michigan	RCV000211000	SCV000267743	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000218227	SCV000277867	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-30	criteria provided, single submitter	clinical testing	The p.V387F variant (also known as c.1159G>T), located in coding exon 9 of the BRCA2 gene, results from a G to T substitution at nucleotide position 1159. The valine at codon 387 is replaced by phenylalanine, 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.
Invitae	RCV000462241	SCV000549481	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 387 of the BRCA2 protein (p.Val387Phe). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 225737). 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. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284070	SCV001469656	uncertain significance	not provided	2020-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001284070	SCV002558072	uncertain significance	not provided	2022-07-26	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 1387G>T
University of Washington Department of Laboratory Medicine, University of Washington	RCV000218227	SCV003849881	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).
PreventionGenetics, part of Exact Sciences	RCV004529015	SCV004111584	uncertain significance	BRCA2-related disorder	2023-06-08	criteria provided, single submitter	clinical testing	The BRCA2 c.1159G>T variant is predicted to result in the amino acid substitution p.Val387Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0064% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32906774-G-T). In ClinVar, this variant is classified as a variant of uncertain significance by the majority of clinical labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/225737/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Color Diagnostics, LLC DBA Color Health	RCV000218227	SCV004361214	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with phenylalanine at codon 387 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 2/250168 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.
MGZ Medical Genetics Center	RCV003607257	SCV004543908	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR
All of Us Research Program, National Institutes of Health	RCV000211000	SCV004846871	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces valine with phenylalanine at codon 387 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 2/250168 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.