ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1567C>T (p.Arg523Cys) (rs147480076)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165016 SCV000215711 likely benign Hereditary cancer-predisposing syndrome 2018-11-29 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Other data supporting benign classification;Other strong data
Invitae RCV000229869 SCV000285938 uncertain significance MYH-associated polyposis 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 523 of the MUTYH protein (p.Arg523Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs147480076, ExAC 0.01%). This variant has been reported in the literature in an individual with colon polyposis (PMID: 27829682). ClinVar contains an entry for this variant (Variation ID: 185573). 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 cysteine 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. 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.
PreventionGenetics,PreventionGenetics RCV000679426 SCV000806348 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000165016 SCV000902831 likely benign Hereditary cancer-predisposing syndrome 2016-10-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000679426 SCV001147262 uncertain significance not provided 2021-01-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175587 SCV001339223 uncertain significance not specified 2020-09-04 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1567C>T (p.Arg523Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251480 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (9.1e-05 vs 0.0046), allowing no conclusion about variant significance. c.1567C>T has been reported in the literature in sequencing studies of individuals affected with a suspected diagnosis of MUTYH-associated Polyposis and among patients with colorectal cancer (example, Ricci_2017, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3; likely benign, n=2) . Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679426 SCV001470029 uncertain significance not provided 2019-12-19 criteria provided, single submitter clinical testing

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