Submissions for variant NM_000059.4(BRCA2):c.1897A>G (p.Asn633Asp)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002820189	SCV003204872	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-09-20	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. 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 asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 633 of the BRCA2 protein (p.Asn633Asp).
University of Washington Department of Laboratory Medicine, University of Washington	RCV003157256	SCV003846372	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).
Ambry Genetics	RCV003157256	SCV005025286	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	The p.N633D variant (also known as c.1897A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1897. The asparagine at codon 633 is replaced by aspartic acid, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004999814	SCV005624338	uncertain significance	not provided	2023-12-05	criteria provided, single submitter	clinical testing	The BRCA2 c.1897A>G (p.Asn633Asp) variant has been reported in the published literature as likely benign in a multifactorial likelihood analysis (PMID: 31131967 (2019)), and is located in a region of the BRCA2 gene that is described as 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.