Submissions for variant NM_000059.4(BRCA2):c.2953A>G (p.Lys985Glu)

dbSNP: rs1555282970

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566817	SCV000661421	uncertain significance	Hereditary cancer-predisposing syndrome	2017-04-04	criteria provided, single submitter	clinical testing	The p.K985E variant (also known as c.2953A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 2953. The lysine at codon 985 is replaced by glutamic acid, an amino acid with similar properties. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000566817	SCV003850264	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003645028	SCV004499913	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-02-27	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 479389). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 985 of the BRCA2 protein (p.Lys985Glu).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV005000236	SCV005624376	uncertain significance	not provided	2024-04-04	criteria provided, single submitter	clinical testing	The BRCA2 c.2953A>G (p.Lys985Glu) variant has been reported in the published literature to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). To the best of our knowledge, this variant has not been reported in individuals with BRCA2-related conditions. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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. Please note that these prediction tools are not fully validated, and therefore, should be viewed with caution. Based on the available information, we are unable to determine the clinical significance of this variant.