Submissions for variant NM_000059.4(BRCA2):c.6725A>G (p.Asp2242Gly)

dbSNP: rs1593909627

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001025579	SCV001187792	uncertain significance	Hereditary cancer-predisposing syndrome	2018-04-13	criteria provided, single submitter	clinical testing	The p.D2242G variant (also known as c.6725A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6725. The aspartic acid at codon 2242 is replaced by glycine, an amino acid with similar properties. This amino acid position is 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862332	SCV002121529	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-06-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with glycine at codon 2242 of the BRCA2 protein (p.Asp2242Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 826580). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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	RCV001025579	SCV003847401	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).