Submissions for variant NM_000059.4(BRCA2):c.4568G>A (p.Gly1523Asp)

dbSNP: rs879255451

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759618	SCV000889052	uncertain significance	not provided	2022-10-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/250510 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 28692638 (2017)). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001312310	SCV001502758	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-12-29	criteria provided, single submitter	clinical testing	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: 619808). This missense change has been observed in individual(s) with ovarian cancer (PMID: 28692638). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1523 of the BRCA2 protein (p.Gly1523Asp). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV003158107	SCV003850619	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).
GeneDx	RCV000759618	SCV003853109	uncertain significance	not provided	2022-09-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with ovarian cancer (Wu et al., 2017); Also known as 4796G>A; This variant is associated with the following publications: (PMID: 35325018, 9002670, 22193408, 30702160, 31825140, 28692638, 32377563, 31911673, 29884841)
Ambry Genetics	RCV003158107	SCV004052545	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-19	criteria provided, single submitter	clinical testing	The p.G1523D variant (also known as c.4568G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 4568. The glycine at codon 1523 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.