Submissions for variant NM_000059.4(BRCA2):c.2951A>G (p.Glu984Gly)

dbSNP: rs767964776

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586715	SCV000694653	uncertain significance	not provided	2016-12-01	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.2951A>G (p.Glu984Gly) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 1/120290 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001867903	SCV002210117	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-03-09	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with breast cancer (PMID: 30415210). ClinVar contains an entry for this variant (Variation ID: 495446). 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. This variant is present in population databases (rs767964776, ExAC 0.01%). 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. This sequence change replaces glutamic acid with glycine at codon 984 of the BRCA2 protein (p.Glu984Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine.
Sema4, Sema4	RCV002255465	SCV002533748	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-21	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV002255465	SCV003850263	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).
Ambry Genetics	RCV002255465	SCV004096094	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-31	criteria provided, single submitter	clinical testing	The p.E984G variant (also known as c.2951A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 2951. The glutamic acid at codon 984 is replaced by glycine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with breast cancer (Lattimore V et al. Breast Cancer Res Treat, 2021 Feb;185:583-590). This amino acid position is poorly 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586715	SCV005624375	uncertain significance	not provided	2024-07-04	criteria provided, single submitter	clinical testing	The BRCA2 c.2951A>G (p.Glu984Gly) variant has been reported in the published literature in individuals with breast cancer (PMID: 33113089 (2021), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). This variant has also been identified in a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). In addition, this variant is located in region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000004 (1/248532 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.