Submissions for variant NM_000059.4(BRCA2):c.7523G>A (p.Gly2508Asp)

dbSNP: rs730881557

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160134	SCV000210427	uncertain significance	not provided	2014-09-03	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.7523G>A at the cDNA level, p.Gly2508Asp (G2508D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGC>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gly2508Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gly2508Asp occurs at a position that is highly conserved across species and is located within the region of interaction with FANCD2 and within the DNA binding domain (UniProt, Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA2 Gly2508Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000509915	SCV000608162	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	clinical testing	The p.G2508D variant (also known as c.7523G>A), located in coding exon 14 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7523. The glycine at codon 2508 is replaced by aspartic acid, an amino acid with similar properties. This alteration was non-functional in a homology directed DNA repair assay (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000160134	SCV001133905	uncertain significance	not provided	2019-02-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000509915	SCV001344653	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001337945	SCV001531565	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2508 of the BRCA2 protein (p.Gly2508Asp). 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: 182241). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 protein function. 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.