Submissions for variant NM_000059.4(BRCA2):c.2963A>G (p.Asp988Gly)

dbSNP: rs876659509

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487113	SCV000567510	uncertain significance	not provided	2015-07-30	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.2963A>G at the cDNA level, p.Asp988Gly (D988G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 3191A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asp988Gly 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 Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asp988Gly occurs at a position that is not conserved and is located in the region of interaction with NPM1 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Asp988Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001017688	SCV001178808	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-16	criteria provided, single submitter	clinical testing	The p.D988G variant (also known as c.2963A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 2963. The aspartic acid at codon 988 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	RCV001340301	SCV001534102	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-27	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 988 of the BRCA2 protein (p.Asp988Gly). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 419600). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001017688	SCV003850275	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).