ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.820C>T (p.Arg274Trp) (rs769237459)

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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 RCV000570778 SCV000662627 likely pathogenic Hereditary cancer-predisposing syndrome 2017-10-24 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,Deficient protein function by in vitro/ex vivo assay,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Color RCV000570778 SCV000690612 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-07 criteria provided, single submitter clinical testing
GeneDx RCV000519616 SCV000617563 likely pathogenic not provided 2017-09-06 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.820C>T at the cDNA level, p.Arg274Trp (R274W) at the protein level,and results in the change of an Arginine to a Tryptophan (CGG>TGG). Also published as MUTYH c.778C>T andArg260Trp (R260W) using alternate nomenclature, this variant has been observed in the compound heterozygous statein at least three individuals with polyposis and/or colorectal cancer, including two siblings (Aceto 2005, Aretz 2006, Vogt2009, Aceto 2015). MUTYH Arg274Trp has also been observed in at least one individual with breast cancer (Tung2016). This variant was described as functionally defective following interrogation in a MutY-Deficient E. colicomplementation assay (Komine 2015). MUTYH Arg274Trp was not observed at a significant allele frequency in largepopulation cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). SinceArginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative aminoacid substitution. MUTYH Arg274Trp occurs at a position that is conserved across species and is not located in aknown functional domain. In silico analyses predict that this variant is probably damaging to protein structure andfunction. Based on currently available evidence, we consider MUTYH Arg274Trp to be a likely pathogenic variant
Invitae RCV000640346 SCV000761935 uncertain significance MYH-associated polyposis 2018-09-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 274 of the MUTYH protein (p.Arg274Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs769237459, ExAC 0.002%). This variant has been reported in compound heterozygosity in several individuals affected with familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), and MUTYH-Associated Polyposis (PMID: 16134147, 25820570, 19732775, 16557584). It has also been reported in an individual affected with breast cancer (PMID: 26976419). This variant is also known as c.778C>T (p.Arg260Trp) in the literature. ClinVar contains an entry for this variant (Variation ID: 449417). Experimental studies have shown that this missense change has non-functional base excision repair (BER) and glycosylase activity (PMID: 25820570). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000640346 SCV000967629 likely pathogenic MYH-associated polyposis 2018-09-18 criteria provided, single submitter clinical testing The p.Arg274Trp variant in MUTYH has been reported in the compound heterozygous state at least 2 individuals with MUTYH-associated polyposis (MAP) who had a sec ond pathogenic variant in MUTYH (Aceto 2005, Aretz 2005, Vogt 2009). Additionall y, it segregated with disease in at least one affected family member (Aceto 2005 ). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 449417) and has been identified in 1/33562 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg274Trp variant may impact protein function (Komine 2 015); however, these types of assays may not accurately represent biological fun ction. Computational prediction tools and conservation analysis support that the p.Arg274Trp variant may impact the protein. In summary, although additional stu dies are required to fully establish its clinical significance, this variant mee ts criteria to be classified as likely pathogenic for autosomal recessive MAP. A CMG/AMP criteria applied: PM2, PM3, PP1, PP3, PS3_Supporting.

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