Submissions for variant NM_000059.4(BRCA2):c.1940G>A (p.Cys647Tyr)

dbSNP: rs1555282368

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575462	SCV000661288	uncertain significance	Hereditary cancer-predisposing syndrome	2017-10-19	criteria provided, single submitter	clinical testing	The p.C647Y variant (also known as c.1940G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 1940. The cysteine at codon 647 is replaced by tyrosine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759583	SCV000888994	uncertain significance	not provided	2018-03-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814757	SCV000955181	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 647 of the BRCA2 protein (p.Cys647Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 479311). 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.
GeneDx	RCV000759583	SCV002013754	uncertain significance	not provided	2019-09-30	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 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 2168G>A; This variant is associated with the following publications: (PMID: 21520333)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000575462	SCV003846398	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).