ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1420C>T (p.Arg474Cys) (rs200229669)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164389 SCV000215025 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Biesecker Lab/Human Development Section,National Institutes of Health RCV000034671 SCV000043367 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Color RCV000164389 SCV000685574 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing
Counsyl RCV000206141 SCV000487322 uncertain significance MYH-associated polyposis 2015-12-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515389 SCV000611406 uncertain significance MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000034671 SCV000293927 uncertain significance not provided 2018-10-12 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1420C>T at the cDNA level, p.Arg474Cys (R474C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant, published as MUTYH 1378C>T using an alternate transcript, was observed in an individual with colorectal cancer (Yurgelun 2017). MUTYH Arg474Cys was observed at an allele frequency of 0.01% (11/126,722) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the NUDIX domain (Ruggieri 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MUTYH Arg474Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two MUTYH pathogenic variants on opposite chromosomes.
Integrated Genetics/Laboratory Corporation of America RCV000780500 SCV000917805 uncertain significance not specified 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.1420C>T (p.Arg474Cys) variant involves the alteration of a nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 12/277240 control chromosomes at a frequency of 0.0000433, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). This variant has been reported in patients with colon cancer or atherosclerosis. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000206141 SCV000259566 uncertain significance MYH-associated polyposis 2018-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 474 of the MUTYH protein (p.Arg474Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs200229669, ExAC 0.007%). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant is also known as c.1378C>T (p.Arg460Cys) in the literature. ClinVar contains an entry for this variant (Variation ID: 41754). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Pathway Genomics RCV000144638 SCV000189965 uncertain significance Carcinoma of colon 2014-07-24 no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034671 SCV000888309 uncertain significance not provided 2018-04-26 criteria provided, single submitter clinical testing

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