ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1495C>G (p.Arg499Gly) (rs137854580)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000472427 SCV000552766 uncertain significance Familial adenomatous polyposis 1 2018-01-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 499 of the APC protein (p.Arg499Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 41518). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000564391 SCV000672537 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000472427 SCV000786129 uncertain significance Familial adenomatous polyposis 1 2018-03-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034403 SCV000888718 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing
Color RCV000564391 SCV000911387 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780856 SCV000918474 uncertain significance not specified 2018-12-03 criteria provided, single submitter clinical testing Variant summary: APC c.1495C>G (p.Arg499Gly) results in a non-conservative amino acid change located in the Armadillo repeats of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 246042 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1495C>G has been reported in the literature in one individual affected with atherosclerosis (Johnston_2012). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034403 SCV000043110 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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