Submissions for variant NM_000059.4(BRCA2):c.4567G>A (p.Gly1523Ser)

dbSNP: rs587781418

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129287	SCV000184048	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-10	criteria provided, single submitter	clinical testing	The p.G1523S variant (also known as c.4567G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 4567. The glycine at codon 1523 is replaced by serine, an amino acid with 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	RCV000506395	SCV000600595	uncertain significance	not specified	2017-05-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129287	SCV000683630	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1523 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 0/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008239). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001204428	SCV001375634	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1523 of the BRCA2 protein (p.Gly1523Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 140987). 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.
Genetic Services Laboratory, University of Chicago	RCV000506395	SCV002071914	uncertain significance	not specified	2021-10-11	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in individuals with BRCA2-related disorders and has also not been described in the population databases such as ExAC and gnomAD. The p.Gly1523Ser change affects a highly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Gly1523Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Gly1523Ser change remains unknown at this time.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129287	SCV003850617	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).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000506395	SCV004027427	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing