ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160751 SCV000216757 pathogenic Hereditary cancer-predisposing syndrome 2017-12-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Deficient protein function by in vitro/ex vivo assay
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.
Integrated Genetics/Laboratory Corporation of America RCV000780505 SCV000917811 likely pathogenic MUTYH-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.
Invitae RCV000701601 SCV000830411 uncertain significance MYH-associated polyposis 2018-08-05 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). This variant is also known as Trp117Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 182688). Experimental studies have shown that this missense change affects mutation rate in E. coli (PMID: 25820570). The clinical significance of this finding is unknown. 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.

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