Submissions for variant NM_000059.4(BRCA2):c.5131G>A (p.Val1711Ile)

dbSNP: rs587782067

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130552	SCV000185422	uncertain significance	Hereditary cancer-predisposing syndrome	2017-07-18	criteria provided, single submitter	clinical testing	The p.V1711I variant (also known as c.5131G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5131. The valine at codon 1711 is replaced by isoleucine, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586102	SCV000694830	uncertain significance	not provided	2016-11-28	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.5131G>A (p.Val1711Ile) variant causes a missense change involving a non-conserved nucleotide, which 4/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications. Although, a clinical diagnostic laboratory and database cite the variant as "uncertain signficance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797822	SCV000937404	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1711 of the BRCA2 protein (p.Val1711Ile). This variant is not present in population databases (gnomAD no frequency). 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: 141863). 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	RCV000130552	SCV001734884	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-24	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1711 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 hereditary cancer 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130552	SCV003847017	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586102	SCV005624447	uncertain significance	not provided	2024-09-11	criteria provided, single submitter	clinical testing	The BRCA2 c.5131G>A (p.Val1711Ile) variant has been reported in the published literature 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.