ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.502C>T (p.Arg168Cys) (rs747993448)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166998 SCV000217819 pathogenic Hereditary cancer-predisposing syndrome 2018-10-19 criteria provided, single submitter clinical testing The p.R182C pathogenic mutation (also known as c.544C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide position 544. The arginine at codon 182 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been previously identified in conjunction with the c.1437_1439del MUTYH mutation in an individual with 100-1000 polyps and with the p.Y179C MUTYH mutation in two unrelated patients with colon cancer and multiple polyps (De Rosa M et al. Dis Colon Rectum. 2009 Feb;52(2):268-74; Wang L et al. Gastroenterology. 2004 Jul;127(1):9-16; Cattaneo F et al. Genet. Med. 2007 Dec;9(12):836-41). Furthermore, this alteration was reportedly determined to be detected in trans with a pathogenic MUTYH mutation in one patient (Universal Mutation Database [available from www.umd.be]). This alteration has also been identified in a monoallelic state in two individuals with colorectal cancer and/or adenomatous polyps, both of whom met Amsterdam criteria (Morak M et al. Eur. J. Cancer. 2011 May;47(7):1046-55; Steinke V et al. Eur. J. Hum. Genet. 2008 May; 16(5):587-92). A functional complementation assay classified this alteration as defective (Komine K et al. Hum Mutat. 2015 Jul;36(7):704-11). In addition, a different disease causing mutation, p.R182H, has also been described at this same location. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Of note, this mutation is also designated as p.R168C in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation.
Invitae RCV000229525 SCV000285955 pathogenic MYH-associated polyposis 2020-10-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 182 of the MUTYH protein (p.Arg182Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs747993448, ExAC <0.01%). This variant has been reported in several individuals affected with MUTYH-associated adenomatous polyposis and colorectal cancer (PMID:21195604, 18091433, 16890597, 19279422, 15236166, 18301448). This variant is also known as p.Arg168Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 187280). Experimental studies have shown that this variant impairs the DNA repair activity of the MUTYH protein (PMID: 25820570). It is located in a functionally important domain of the MUTYH protein (PMID: 15236166) and a different missense substitution at this codon (p.Arg182His) has been determined to be pathogenic (PMID: 20848659, 23322991). This further indicates that the arginine residue is important for MUTYH protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000236750 SCV000293495 pathogenic not provided 2018-03-20 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.544C>T at the cDNA level, p.Arg182Cys (R182C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). MUTYH Arg182Cys, also annotated as Arg168Cys using a different gene transcript, has been identified in the compound heterozygous state with a second pathogenic MUTYH variant in several individuals with a personal history consistent with MUTYH-associated polyposis (Wang 2004, Di Gregorio 2006, Cattaneo 2007, De Rosa 2009). On functional interrogation, this variant demonstrated defective base excision repair activity in a yeast-based complementation assay (Komine 2015). MUTYH Arg182Cys 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.
Counsyl RCV000229525 SCV000678196 likely pathogenic MYH-associated polyposis 2016-12-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166998 SCV001347956 pathogenic Hereditary cancer-predisposing syndrome 2021-01-12 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 182 of the MUTYH protein. This variant is also known as c.502C>T (p.Arg168Cys) in the literature based on a different transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that the mutant protein is unable to complement MutY-deficient bacterial cells (PMID: 25820570). This variant has been reported in individuals affected with multiple adenomatous polyposis in compound heterozygous state with a known pathogenic variant (PMID: 15236166, 16890597, 18091433). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same amino acid position, NM_001128425.2:c.545G>A (p.Arg182His) (a.k.a. NM_001048174.2:c.461G>A (p.Arg154His)) is known to be disease-causing (ClinVar variation ID: 182689), indicating that arginine at this position is important for MUTYH function. Based on the available evidence, this variant is classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000229525 SCV001429582 pathogenic MYH-associated polyposis 2018-03-15 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000236750 SCV001447072 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000236750 SCV001554005 pathogenic not provided no assertion criteria provided clinical testing The MUTYH p.Arg182Cys variant was identified in 5 of 1204 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer, and was not identified in 2444 control chromosomes from healthy individuals (Cattaneo 2007, De Rosa 2009, Di Gregorio 2006, Olschwang 2007, Steinke 2008). The variant was also identified in dbSNP (ID: rs747993448) as “With Pathogenic allele”, Clinvitae database (classified as pathogenic by Invitae and likely pathogenic by ClinVar), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as pathogenic by Ambry Genetics and Invitae; classified as likely pathogenic by GenDx) and UMD (2x with a “likely causal” classification). In UMD the variant was identified with a co-occurring pathogenic MUTYH variant (c.494A>G, p.Tyr165Cys) increasing the likelihood that the variant has clinical significance. The p.Arg182 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, the variant was identified in patients as one of the biallelic missense variants along with: c.494A>G, p.Tyr165Cys predicted to severely impair the MUTYH protein function (Cattaneo 2007) and c.1395_97delGGA, p.466delE in a patient with classical polyposis phenotype with recessive inheritance (De Rosa 2009). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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