Submissions for variant NM_000059.4(BRCA2):c.6448A>C (p.Lys2150Gln)

dbSNP: rs1403648108

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000565008	SCV000665141	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-07	criteria provided, single submitter	clinical testing	The p.K2150Q variant (also known as c.6448A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 6448. The lysine at codon 2150 is replaced by glutamine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Han SH et al. Clin Genet, 2006 Dec;70:496-501; Kim BY et al. Biochem Biophys Res Commun, 2006 Oct;349:604-10; Seong MW et al. Clin Genet, 2009 Aug;76:152-60). 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.
Counsyl	RCV000662567	SCV000785170	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858157	SCV002236584	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2150 of the BRCA2 protein (p.Lys2150Gln). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 17100994, 30415210, 32467295). ClinVar contains an entry for this variant (Variation ID: 481041). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
GeneDx	RCV001724066	SCV002818892	uncertain significance	not provided	2022-12-28	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; Also known as 6676A>C; Observed in individuals with breast or gynecologic cancer (Han et al., 2006; Kim et al., 2006; Seong et al., 2009; Ha et al., 2020); This variant is associated with the following publications: (PMID: 17100994, 19656164, 16949048, 32467295, 30415210, 29884841, 32377563, 33078592)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000565008	SCV003852538	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).
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001724066	SCV001953846	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001724066	SCV001975605	likely benign	not provided		no assertion criteria provided	clinical testing