Submissions for variant NM_000059.4(BRCA2):c.5230A>G (p.Ser1744Gly)

dbSNP: rs587778121

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563678	SCV000661323	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-10	criteria provided, single submitter	clinical testing	The p.S1744G variant (also known as c.5230A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5230. The serine at codon 1744 is replaced by glycine, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001039614	SCV001203151	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1744 of the BRCA2 protein (p.Ser1744Gly). 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: 133730). 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.
Sema4, Sema4	RCV000563678	SCV002536116	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-28	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000563678	SCV003847098	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477498	SCV004219679	uncertain significance	not provided	2023-06-09	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in healthy individuals (PMID: 24728327 (2014)). In addition, the variant has been identified in a study of BRCA1 and BRCA2 regions without essential functions that tolerate variation (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.
Color Diagnostics, LLC DBA Color Health	RCV000563678	SCV004362097	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 1744 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. 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.
ITMI	RCV000120323	SCV000084475	not provided	not specified	2013-09-19	no assertion provided	reference population