Submissions for variant NM_000059.4(BRCA2):c.6677A>G (p.Glu2226Gly)

dbSNP: rs1281267586

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528701	SCV000635520	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2226 of the BRCA2 protein (p.Glu2226Gly). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 462410). 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.
Ambry Genetics	RCV000569289	SCV000668857	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-25	criteria provided, single submitter	clinical testing	The p.E2226G variant (also known as c.6677A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6677. The glutamic acid at codon 2226 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly 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.
GeneDx	RCV002280124	SCV002568550	uncertain significance	not provided	2022-08-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
University of Washington Department of Laboratory Medicine, University of Washington	RCV000569289	SCV003847354	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).