Submissions for variant NM_000059.4(BRCA2):c.5867A>T (p.Asp1956Val)

dbSNP: rs1309562690

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563256	SCV000668736	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-26	criteria provided, single submitter	clinical testing	The p.D1956V variant (also known as c.5867A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 5867. The aspartic acid at codon 1956 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, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637411	SCV000758867	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1956 of the BRCA2 protein (p.Asp1956Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 32438681). ClinVar contains an entry for this variant (Variation ID: 483068). 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 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	RCV000563256	SCV001358177	uncertain significance	Hereditary cancer-predisposing syndrome	2020-07-14	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 1956 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 been reported in an individual affected with breast cancer (PMID: 32438681). 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.
GeneDx	RCV001584383	SCV001812134	uncertain significance	not provided	2019-08-12	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; Also known as BRCA2 6095A>T
Sema4, Sema4	RCV000563256	SCV002536180	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000563256	SCV003850737	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).