ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2224C>A (p.Gln742Lys) (rs80358494)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164550 SCV000215206 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000531299 SCV000635212 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-01-12 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 742 of the BRCA2 protein (p.Gln742Lys). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 185181). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on BRCA2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506123 SCV000600504 uncertain significance not specified 2017-03-16 criteria provided, single submitter clinical testing

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