Submissions for variant NM_000059.4(BRCA2):c.1063G>A (p.Val355Ile)

dbSNP: rs2072403612

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001755256	SCV002005333	uncertain significance	not provided	2019-09-26	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 that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31131967)
Ambry Genetics	RCV002414329	SCV002710937	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-14	criteria provided, single submitter	clinical testing	The p.V355I variant (also known as c.1063G>A), located in coding exon 9 of the BRCA2 gene, results from a G to A substitution at nucleotide position 1063. The valine at codon 355 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.
Invitae	RCV002540609	SCV002972021	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-23	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 1315594). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 355 of the BRCA2 protein (p.Val355Ile).
University of Washington Department of Laboratory Medicine, University of Washington	RCV002414329	SCV003849814	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).