ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1214C>T (p.Pro405Leu) (rs529008617)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131914 SCV000186969 pathogenic Hereditary cancer-predisposing syndrome 2018-01-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000722033 SCV000853210 pathogenic B lymphoblastic leukemia lymphoma, no ICD-O subtype 2017-04-04 criteria provided, single submitter clinical testing This is a missense alteration in which a C is replaced by a T at coding nucleotide 1214 and is predicted to change a Proline to a Leucine at amino acid codon 405. Classification criteria: PS3, PM2, PM3, PP3, PP5.
Color RCV000131914 SCV000685555 pathogenic Hereditary cancer-predisposing syndrome 2016-09-19 criteria provided, single submitter clinical testing
Counsyl RCV000191934 SCV000678195 pathogenic MYH-associated polyposis 2017-01-17 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000191934 SCV000592712 pathogenic MYH-associated polyposis 2013-01-02 criteria provided, single submitter clinical testing
GeneDx RCV000413961 SCV000490629 pathogenic not provided 2018-12-21 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1214C>T at the cDNA level, p.Pro405Leu (P405L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). MUTYH Pro405Leu, also denoted as Pro391Leu and Pro377Leu using alternate nomenclature, has been published in the literature as a Dutch founder variant, and when found in the homozygous state or in combination with another pathogenic MUTYH variant, is known to cause MUTYH-associated polyposis (MAP) (Nielsen 2005, Aretz 2006, Kanter-Smoler 2006, Bouguen 2007, Vogt 2009, Morak 2010, Wasielewski 2010). Multiple in vivo and in vitro functional studies demonstrate that MUTYH Pro405Leu is associated with severely impaired glycosylase activity and severely suppressed oxidative mutagenesis (Kundu 2009, Goto 2010, Shinmura 2012). MUTYH Pro405Leu was observed at an allele frequency of 0.013% (16/126,332) 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, we consider this variant to be pathogenic.
GeneReviews RCV000191934 SCV000246166 pathogenic MYH-associated polyposis 2015-09-24 no assertion criteria provided literature only
Illumina Clinical Services Laboratory,Illumina RCV000191934 SCV000915415 pathogenic MYH-associated polyposis 2018-12-13 criteria provided, single submitter clinical testing The MUTYH c.1172C>T (p.Pro391Leu) is a missense variant. Across a selection of the available literature, the p.Pro391Leu variant has been found in 19 individuals affected with polyposis, including six in a homozygous state and 13 in a compound heterozygous state (Kanter-Smoler G et al. 2006; Nielsen et al. 2005; Aretz et al. 2006; Middeldorp et al. 2008). The variant was absent from 424 control alleles and is reported at a frequency of 0.000183 in the European (non-Finnish) population of the Exome Aggregation Consortium (Kanter-Smoler G et al. 2006; Aretz et al. 2006). Functional studies demonstrated the variant resulted in severely impaired glycosylase activity (Kundu et al. 2009; Goto et al. 2010) and mutation suppression compared to wild type (Kundu et al. 2009; Shinmura et al. 2012; Komine et al. 2015). The Pro391 residue is conserved across species and is located in a functionally important domain (Kundu et al. 2009). Based on the collective data, the p.Pro391Leu variant is classified as pathogenic for MYH-associated polyposis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000191934 SCV000285918 pathogenic MYH-associated polyposis 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 405 of the MUTYH protein (p.Pro405Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs529008617, ExAC 0.02%). This variant is clearly defined as a MUTYH-associated polyposis causative allele (PMID: 16140997, 16557584, 16616356, 19732775). It is a founder mutation in the Dutch population. This variant is also known as 1172C>T, P391L, and P377L in the literature. ClinVar contains an entry for this variant (Variation ID: 142604). Experimental studies have shown that this missense change severely impacts protein function (PMID: 19836313, 20848659, 25820570, 23322991). For these reasons, this variant has been classified as Pathogenic.
Pathway Genomics RCV000144633 SCV000189960 pathogenic Carcinoma of colon 2014-07-24 no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000413961 SCV000601629 pathogenic not provided 2017-05-12 criteria provided, single submitter clinical testing

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