ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.461G>A (p.Arg154His) (rs143353451)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160752 SCV000211402 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.545G>A at the cDNA level, p.Arg182His (R182H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). Using alternate nomenclature, this variant has been previously published as MUTYH R168H and R154H. MUTYH Arg182His has been seen in multiple individuals as compound heterozygotes with known pathogenic variants and a phenotype consistent with MUTYH-associated polyposis (MAP) (Isidro 2004, Aretz 2006, Di Gregorio 2006, Nielsen 2009, Morak 2010). In addition, several functional assays have determined that this variant severely affects glycosylation and suppresses oxidative mutagenesis (Goto 2010, Shinmura 2012, Komine 2015). MUTYH Arg182His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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.
Invitae RCV000200700 SCV000253867 pathogenic MYH-associated polyposis 2020-10-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 182 of the MUTYH protein (p.Arg182His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs143353451, ExAC <0.01%). This variant has been observed in individuals affected with MUTYH-associated polyposis. In these cases this variant was found in compound heterozygosity with a pathogenic MUTYH variant (PMID: 15366000, 16557584, 20618354, 19394335, 19032956). This variant is also known as R154H and R168H in the literature. ClinVar contains an entry for this variant (Variation ID: 182689). Experimental studies have shown that this missense change disrupts the DNA glycosylase activity (PMID: 20848659) and mutation suppressive activity of the MUTYH protein (PMID: 23322991). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000214896 SCV000273003 pathogenic Hereditary cancer-predisposing syndrome 2019-03-17 criteria provided, single submitter clinical testing ​The p.R182H pathogenic mutation (also known as c.545G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 545. The arginine at codon 182 is replaced by histidine, an amino acid with highly similar properties. This pathogenic mutation has been identified in trans in several individuals with MAP phenotypes (Isidro et al. Hum Mutat 2004 Oct; 24(4):353-4; Di Gregorio et al. Gastroenterology 2006 Aug; 131(2):439-44; Aretz et al. Int J Cancer 2006 Aug 15;119(4): 807-14; Jones N et al. Gastroenterology. 2009 Aug;137(2):489-94, 494.e1; Morak M et al. Clin Genet. 2010 Oct;78(4):353-63). In vitro studies comparing wild-type protein and variant-type proteins demonstrated severely impaired DNA glycosylase activity associated with the p.R182H alelle (Goto et al. Hum Mutat 2010 Nov; 31(11):E1861-74). This alteration has also been reported as functionally defective by one group based on results of a site-directed mutagenesis E. coli study (Komine K et al. Hum. Mutat., 2015 Jul;36:704-11). Of note, this mutation is also designated as p.R168H in published literature. Based on the majority of available evidence to date, this alteration is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508179 SCV000604307 pathogenic not specified 2016-11-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000214896 SCV000685639 pathogenic Hereditary cancer-predisposing syndrome 2020-05-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000200700 SCV000697702 pathogenic MYH-associated polyposis 2019-01-29 criteria provided, single submitter clinical testing Variant summary: The variant, MUTYH c.545G>A (p.Arg182His) 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 8.1e-06 in 246268 control chromosomes (gnomAD). The variant, c.545G>A has been reported in the literature in multiple individuals affected with Attenuated familial adenomatous polyposis and colorectal cancer (Morak_2010, Komine_2015, AlDubayan_2018, Yugelun_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Shinmura_2012). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics RCV000200700 SCV000837774 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160752 SCV001470576 pathogenic not provided 2020-06-30 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Other pathogenic or likely pathogenic variants affect the same amino acid . In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Genomics England Pilot Project,Genomics England RCV000200700 SCV001760035 pathogenic MYH-associated polyposis no assertion criteria provided clinical testing

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