Submissions for variant NM_000059.4(BRCA2):c.6298C>A (p.Gln2100Lys)

dbSNP: rs746661607

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566896	SCV000668642	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-23	criteria provided, single submitter	clinical testing	The p.Q2100K variant (also known as c.6298C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 6298. The glutamine at codon 2100 is replaced by lysine, 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	RCV000637615	SCV000759081	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 2100 of the BRCA2 protein (p.Gln2100Lys). This variant is present in population databases (rs746661607, 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: 483017). 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. 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.
GeneDx	RCV002508231	SCV002817459	uncertain significance	not provided	2022-07-01	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; Also known as 6526C>A
University of Washington Department of Laboratory Medicine, University of Washington	RCV000566896	SCV003852404	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).