ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.391T>A (p.Trp131Arg) (rs730881832)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212700 SCV000211401 pathogenic not provided 2017-12-15 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.391T>A at the cDNA level, p.Trp131Arg (W131R) at the protein level, and results in the change of a Tryptophan to an Arginine (TGG>AGG). This variant, also known as MUTYH Trp117Arg based on an alternate transcript, has been reported in at least one individual with adenomatous polyposis who was also found to carry the known pathogenic p.Tyr179Cys variant (Sampson 2003, Vogt 2009). This variant was considered functionally defective based on results of a complementation assay in E. coli (Komine 2015). MUTYH Trp131Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Tryptophan and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MUTYH Trp131Arg occurs at a position that is conserved across species and is not located in a known functional domain. Protein-based in silico analyses predict that this variant is probably damaging to protein structure and function. Additionally, multiple splicing models predict that this variant may create a cryptic splice acceptor site and/or weaken the nearby natural splice acceptor site and lead to abnormal splicing. However, in the absence of RNA studies, the actual effect of this variant on splicing is unknown. Based on currently available evidence, we consider MUTYH Trp131Arg to be a pathogenic variant.
Ambry Genetics RCV000160751 SCV000216757 pathogenic Hereditary cancer-predisposing syndrome 2017-12-19 criteria provided, single submitter clinical testing The p.W131R pathogenic mutation (also known as c.391T>A) is located in coding exon 5 of the MUTYH gene. This alteration results from a T to A substitution at nucleotide position 391. The tryptophan at codon 131 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in conjunction with the MUTYH p.Y179C pathogenic mutation in an individual with 152 colorectal polyps diagnosed at age 30 (Sampson JR et al. Lancet 2003 Jul; 362(9377):39-41; Vogt S et al. Gastroenterology 2009 Dec; 137(6):1976-85.e1-10). It was also detected in a patient diagnosed with colon cancer and colon polyps who underwent multi-gene panel testing (Susswein LR et al. Genet Med. 2016 Aug;18(8):823-32). Functional and structural assays demonstrated that this alteration is functionally defective and predicted to disrupt DNA-binding ability (David SS et al. Nature 2007 Jun;447(7147):941-50; Komine K et al. Hum Mutat. 2015 Jul;36(7):704-11). This alteration is also known as p.W117R in the published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000701601 SCV000830411 likely pathogenic MYH-associated polyposis 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 131 of the MUTYH protein (p.Trp131Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs730881832, ExAC 0.001%). This variant has been reported in individuals affected with colon cancer and MUTYH-associated polyposis (PMID: 12853198, 19394335, 19732775, 26681312, 25820570, 19032956, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Trp117Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 182688).Ôªø This variant has been reported to affect MUTYH protein function (PMID: 25820570). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000701601 SCV000917811 likely pathogenic MYH-associated polyposis 2018-11-05 criteria provided, single submitter clinical testing Variant summary: MUTYH c.391T>A (p.Trp131Arg) results in a non-conservative amino acid change located in the HhH-GPD domain 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 4.1e-06 in 246194 control chromosomes (gnomAD). c.391T>A has been reported in the literature in individuals affected with MUTYH-associated Polyposis (Jones_2009, Sampson_2003). These data indicate that the variant may be associated with disease. A functional study, Komine_2015, found the variant to be defective in base excision repair in a MUTY-deficient Ecoli complementation assay. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Health, Inc RCV000160751 SCV001343955 likely pathogenic Hereditary cancer-predisposing syndrome 2019-06-21 criteria provided, single submitter clinical testing

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