Submissions for variant NM_000059.4(BRCA2):c.2224C>A (p.Gln742Lys)

dbSNP: rs80358494

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164550	SCV000215206	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	The p.Q742K variant (also known as c.2224C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 2224. The glutamine at codon 742 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590224	SCV000600504	uncertain significance	not provided	2018-11-09	criteria provided, single submitter	clinical testing
Invitae	RCV000531299	SCV000635212	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-06	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 742 of the BRCA2 protein (p.Gln742Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 185181). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590224	SCV000694598	uncertain significance	not provided	2017-04-30	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.2224C>A (p.Gln742Lys) variant involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict a benign outcome for this variant. However, these predictions have yet to be confirmed by functional studies. This variant is absent in the large control database ExAC (0/121156 control chromosomes). In addition, a clinical diagnostic laboratory has classified this variant as uncertain significance. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been 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.
GeneDx	RCV000590224	SCV002028797	uncertain significance	not provided	2021-11-29	criteria provided, single submitter	clinical testing	Observed with a truncating BRCA2 variant in a patient with Fanconi anemia (Castella 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (Lek 2016); Also known as 2452C>A; This variant is associated with the following publications: (PMID: 21273304)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164550	SCV003846589	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).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590224	SCV004563800	uncertain significance	not provided	2023-09-19	criteria provided, single submitter	clinical testing	The BRCA2 c.2224C>A; p.Gln742Lys variant (rs80358494), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 185181). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.331). Due to limited information, the clinical significance of this variant is uncertain at this time.
All of Us Research Program, National Institutes of Health	RCV003995347	SCV004847021	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-31	criteria provided, single submitter	clinical testing