ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1249C>T (p.Arg417Cys) (rs773370513)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164662 SCV000215327 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-19 criteria provided, single submitter clinical testing The p.R417C variant (also known as c.1249C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1249. The arginine at codon 417 is replaced by cysteine, an amino acid with highly dissimilar 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.
Invitae RCV000233366 SCV000285919 uncertain significance MYH-associated polyposis 2020-08-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 417 of the MUTYH protein (p.Arg417Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs773370513, ExAC 0.02%). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 185272). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C1). 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. 5
GeneDx RCV000656911 SCV000565262 uncertain significance not provided 2018-04-25 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1249C>T at the cDNA level, p.Arg417Cys (R417C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in an endometrial and colon cancer sample (Forbes 2014). MUTYH Arg417Cys was not observed at a significant allele frequency 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 Arg417Cys 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482719 SCV000601631 uncertain significance not specified 2017-01-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000482719 SCV001363478 uncertain significance not specified 2019-03-18 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1249C>T (p.Arg417Cys) results in a non-conservative amino acid change located in the MutY, C-terminal/NUDIX hydrolase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 276912 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1249C>T in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Four 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.

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