ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.241C>T (p.Arg81Trp) (rs765123255)

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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 RCV000162761 SCV000213238 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing ​The p.R109W variant (also known as c.325C>T), located in coding exon 3 of the MUTYH gene, results from a C to T substitution at nucleotide position 325. The arginine at codon 109 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been identified, in conjunction with a pathogenic MUTYH mutation, in multiple patients with colorectal cancer and/or polyposis (Vogt et al. Gastroenterology. 2009;137:1976–1985; Yurgelun MB et al. Gastroenterology 2015 Sep;149:604-13.e20; Church J et al. Dis. Colon Rectum, 2016 Jun;59:565). This alteration was also identified in 1 of 34 patients with colorectal cancer under age 43 from a cohort of 685 Japanese patients and was associated with severely reduced MUTYH protein function (Shinmura K et al. Oxid Med Cell Longev 2014;2014:617351). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000230772 SCV000285944 pathogenic MYH-associated polyposis 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 109 of the MUTYH protein (p.Arg109Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs765123255, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with MUTYH-associated polyposis and colorectal cancer (CRC) (PMID: 19732775, 21520333). It also co-occurred with a pathogenic variant in an individual affected with suspected Lynch syndrome (PMID: 25980754), and was reported as heterozygous in an individual affected with early-onset CRC (PMID: 24799981). ClinVar contains an entry for this variant (Variation ID: 183896). Experimental studies have shown that this missense change disrupts the DNA glycosylase activity of the MUTYH protein in vitro, and its ability to suppress mutations in vivo (PMID: 24799981). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000442590 SCV000517270 pathogenic not provided 2018-04-26 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.325C>T at the cDNA level, p.Arg109Trp (R109W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant, also published as c.283C>T, Arg95Trp and R81W using alternate transcripts, has been co-observed with the common pathogenic variant MUTYH Gly396Asp in a patient with colorectal cancer and 50 to 100 colorectal polyps (Vogt 2009) and in a patient with a Lynch syndrome-associated cancer and/or colon polyps (Yurgelun 2015). In addition, this variant has been observed to occur in trans with a pathogenic MUTYH variant in multiple individuals with clinical features suggestive of MUTYH-associated polyposis at this laboratory. MUTYH Arg109Trp was associated with decreased DNA glycosylase activity and decreased ability to suppress 8-hydroxyguanine-induced mutations compared to wild type in functional studies using human cell lines (Shinmura 2014). MUTYH Arg109Trp was observed at an allele frequency of 0.006% (2/30782) in individuals of South Asian ancestry 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 the currently available information, we consider MUTYH Arg109Trp to be a pathogenic variant. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000230772 SCV000538049 likely pathogenic MYH-associated polyposis 2016-03-30 criteria provided, single submitter clinical testing The c.325C>T (p.Arg109Trp) missense variant in the MUTYH gene has been previously reported in multiple individuals affected with Familial Adenomatous Polyposis (Vogt et al., 2009; Shinmura et al., 2014; Nielsen M et al., 2009). In two unrelated individuals, this variant was observed in trans with a known pathogenic variant, Gly396Asp (Vogt et al., 2009; Yurgelun MB et al., 2015). Furthermore, an in vitro functional assay demonstrated that this variant resulted in reduced DNA glycosylase activity and impaired mutation-suppression activity (Shinmura et al., 2014). This variant is reported at low frequency in the population databases (Exome Sequencing Project = NA; 1000 Genomes = NA; and ExAC = 0.006%). Multiple in silico algorithms predict this variant to have a deleterious effect (CADD = 15.47; PolyPhen = 1.0; SIFT = 0.0). Ambry Genetics has classified this variant as Likely pathogenic. Therefore, this collective evidence supports the classification of the c.325C>T (p.Arg109Trp) as a recessive Likely pathogenic variant for Familial Adenomatous Polyposis.
Counsyl RCV000230772 SCV000678193 likely pathogenic MYH-associated polyposis 2015-09-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162761 SCV000690558 likely pathogenic Hereditary cancer-predisposing syndrome 2020-11-23 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 109 of the MUTYH protein. 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 this variant disrupts the DNA glycosylase activity of the MUTYH protein and its ability to suppress mutations (PMID: 24799981). This variant has been reported in compound heterozygous state with a pathogenic variant in an individual affected with MUTYH-associated polyposis and colorectal cancer (PMID: 19394335, 19527492, 19732775) and in an individual suspected of having Lynch syndrome (PMID: 25980754). This variant has also been observed in a heterozygous individual affected with early-onset colorectal cancer (PMID: 24799981). This variant has been identified in 11/282856 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000230772 SCV000697691 likely pathogenic MYH-associated polyposis 2015-10-16 criteria provided, single submitter clinical testing
Mendelics RCV000230772 SCV000837782 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000442590 SCV001134475 likely pathogenic not provided 2018-10-24 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000230772 SCV001499742 likely pathogenic MYH-associated polyposis 2020-04-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353971 SCV000592680 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Arg109Trp variant was identified in 2 of 438 proband chromosomes (frequency: 0.005) from Euorpean and Japanese individuals or families with MAP or early onset colorectal cancer (Nielsen 2009, Shinmura 2014); The variant was not identified in dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), MutDB, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight VariantWire database, UMD and COSMIC; nor was it previously identified in our laboratory. The variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 6 of 121394 chromosomes (all heterozygotes; frequency: 4.94E-05) from a population of European (Non-Finnish) (4/66728 individuals) and South Asian (2/16512) individuals, but not in East Asian, African, Latino or European (Finnish) individuals; the variant was also identified in the InSiGHT Colon Cancer Gene Variant Database (3x) and HGMD. The p.Arg109 residue is conserved across mammals and lower organisms, and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp (Tryptophan) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The p.Arg109Trp variant was identified in a Japanese early onset CRC patient (heterozygous germline, and not biallelic for MUTYH), and studies using DNA cleavage and supF forward mutation assays showed functional impairment through defective DNA glycosylase activity and impaired suppressive activity against mutations (Shinmura 2014). In a Dutch study evaluating histological and molecular aspects of MAP tumours, it was found that these tumours show similarities to sporadic and Lynch tumors. The variant co-occurred with the pathogenic p.Gly396Asp (Nielsen 2009). An additional European study looking at incidence of both malignant and benign extracolonic lesions in MAP patients, the variant co-occurred with the pathogenic p.Gly396Asp. (Vogt 2009) increasing the likelihood this variant is clinically significant. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic.

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