ClinVar Genomic variation as it relates to human health

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.

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 the compound heterozygous state in individuals affected with MUTYH-associated polyposis and colorectal cancer (PMID: 19394335, 19527492, 19732775; ClinVar SCV000517270.5) 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 Pathogenic.

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; Ambry internal data). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.

Observed in the apparently heterozygous state in individuals with Lynch syndrome-associated cancers and/or colon polyps, as well as other cancers (PMID: 17949294, 25980754, 35264596, 34308104); Published functional studies demonstrate a damaging effect: decreased DNA glycosylase activity, decreased ability to suppress 8-hydroxyguanine-induced mutations compared to wild type (PMID: 24799981); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.283C>T, Arg95Trp, and R81W; This variant is associated with the following publications: (PMID: 20725929, 28152038, 19732775, 19032956, 24799981, 17949294, 25980754, 26600934, 26694661, 21520333, 27253753, 19394335, 30604180, 33830941, 34308104, 35264596, 30291343, 32980694)

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.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 109 of the MUTYH protein (p.Arg109Trp). This variant is present in population databases (rs765123255, gnomAD 0.006%). This missense change has been observed in individual(s) with early-onset colorectal cancer, MUTYH-associated polyposis, and/or suspected Lynch syndrome (PMID: 19732775, 21520333, 24799981, 25980754). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 183896). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 24799981). For these reasons, this variant has been classified as Pathogenic.

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.