ClinVar Genomic variation as it relates to human health

The MUTYH variant designated as NM_001128425.1:c.700G>A (p.Val234Met) is classified as likely pathogenic. In one observed family, this variant co-occurs with a known pathogenic variant (MUTYH p.Tyr179Cys or p.Y179C) in MUTYH in five siblings who each have a documented history of multiple colon polyps and/or colon cancer. The variant was shown to be in trans configuration with the MUTYH p.Y179C variant. This genomic position is highly conserved. Experimental studies of this variant have shown that it partially impairs MUTYH protein function (Komine 2015, PMID: 25820570). This variant is listed in population databases and is present in 1/5500 individuals of European descent (exac.broadinstitute.org). Bayesian analysis integrating all of this data (Tavtigian et al, 2018) gives about 98% probability of pathogenicity, which is consistent with a classification of likely pathogenic. MUTYH p.Val234Met is expected to alter MUTYH function and increase the risk of developing colon cancer, multiple colon polyps, and other features of MYH-associated polyposis when it co-occurs with a pathogenic mutation in MUTYH (Morak 2010, PMID 20618354; Grover 2012, PMID: 22851115). This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

This missense variant replaces valine with methionine at codon 234 of the MUTYH protein (NM\_001128425.1). This variant has also been reported as Val206Met in the context of an alternative transcript (NM\_001048174.2). 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 the mutant protein to exhibit a partial defect in DNA mismatch repair assay in a bacterial system (PMID: 25820570) but a near normal DNA mismatch repair activity in human cells despite partially reduced DNA glycosylase activity (PMID: 26694661). This variant has been reported in the compound heterozygous state with two different pathogenic MUTYH variants in two unrelated individuals affected with colorectal polyposis and cancer (PMID: 20618354, 30374176). For one of these probands, the same biallelic mutations were observed in four other siblings also affected with colorectal polyposis and cancer (PMID: 30374176). Additional individuals affected with colorectal polyposis and/or cancer who carried another disease causing variant in the same gene have been reported by external laboratories (ClinVar SCV000211403.14, SCV000186820.7, external communication). This variant has also been observed in heterozygous individuals affected with colorectal cancer (PMID: 14991577, 16774938, 25980754). This variant has been identified in 24/282044 chromosomes (23/128662 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 234 of the MUTYH protein (p.Val234Met). This variant is present in population databases (rs200165598, gnomAD 0.02%). This missense change has been observed in individual(s) with colon cancer and/or clinical features of MUTYH-associated polyposis (MAP) (PMID: 14991577, 16774938, 30374176; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.658G>A (p.Val220Met). ClinVar contains an entry for this variant (Variation ID: 135989). 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: 25820570, 26694661). For these reasons, this variant has been classified as Pathogenic.

The MUTYH c.700G>A; p.Val234Met variant (rs200165598), also known as Val220Met for traditional nomenclature, is reported in the literature in individuals with colorectal cancer but a second MUTYH variant was not identified (Fleischmann 2004, Peterlongo 2006, Yurgelun 2015). Our laboratory has identified this variant previously in an individual with a personal and family history of colon cancer, who also carried a pathogenic MUTYH frameshift variant. One functional study shows that the p.Val234Met variant protein has partially defective function (Komine 2015), while another study shows the variant protein retains normal repair activity (Shinmura 2016). This variant is reported in ClinVar (Variation ID: 135989). It is found in the general European (non-Finnish) population with an allele frequency of 0.02% (23/128662 alleles) in the Genome Aggregation Database. Due to limited information, the significance of this variant is uncertain at this time. REFERENCES Fleischmann C et al. Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer. Int J Cancer. 2004 Apr 20;109(4):554-8. Komine K et al. Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain. Hum Mutat. 2015 Jul;36(7):704-11. Peterlongo P et al. Increased frequency of disease-causing MYH mutations in colon cancer families. Carcinogenesis. 2006 Nov;27(11):2243-9. Shinmura K et al. Functional Evaluation of Nine Missense-Type Variants of the Human DNA Glycosylase Enzyme MUTYH in the Japanese Population. Hum Mutat. 2016 Apr;37(4):350-3. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20.

Observed as heterozygous in individuals with colon cancer as well as in healthy controls (PMID: 16774938, 14991577); Published functional studies demonstrate partially defective base excision repair activity, but DNA glycosylase activity and mutation suppression ability similar to wild-type (PMID: 25820570, 26694661); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as c.658G>A p.(V220M); This variant is associated with the following publications: (PMID: 19725997, 20725929, 14991577, 16774938, 25820570, 15465463, 25980754, 26694661, 28944238, 33436027, 29360161, 26580448, 26377631, 15326180, 9846876, 17581577, 17161978, 35034041, 31422818, 23108399, 11801590, 37357966, 33471991, 38196581, 33850299, 34326862, 30374176, 36744932)

This missense variant replaces valine with methionine at codon 234 of the MUTYH protein (NM_001128425.1). This variant has also been reported as Val206Met in the context of an alternative transcript (NM_001048174.2). 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 the mutant protein to exhibit a partial defect in DNA mismatch repair assay in a bacterial system (PMID: 25820570) but a near normal DNA mismatch repair activity in human cells despite partially reduced DNA glycosylase activity (PMID: 26694661). This variant has been reported in the compound heterozygous state with two different pathogenic MUTYH variants in two unrelated individuals affected with colorectal polyposis and cancer (PMID: 20618354, 30374176). For one of these probands, the same biallelic mutations were observed in four other siblings also affected with colorectal polyposis and cancer (PMID: 30374176). Additional individuals affected with colorectal polyposis and/or cancer who carried another disease causing variant in the same gene in addition to this variant have been reported by external laboratories (ClinVar SCV000211403.14, SCV000186820.7, external communication). This variant has also been observed in heterozygous individuals affected with colorectal cancer (PMID: 14991577, 16774938, 25980754). This variant has been identified in 24/282044 chromosomes (23/128662 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The p.V234M variant (also known as c.700G>A), located in exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 700. The valine at codon 234 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in the heterozygous state in multiple colorectal cancer/polyposis and HNPCC/HNPCC-like cohorts to date (Peterlongo P et al. Carcinogenesis. 2006 Nov;27:2243-9; Fleischmann C et al. Int. J. Cancer. 2004 Apr;109:554-8; DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Gordon AS et al. Am J Hum Genet, 2019 09;105:526-533; Patel SG et al. Hered Cancer Clin Pract, 2021 Jan;19:8). In two studies, it was reported to have at least partial function in bacterial and human cell-line based glycosylase and mutagenesis assays (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11; Shinmura K et al. Hum. Mutat. 2016 Apr;37:350-3). This variant segregated with colon cancer or colon polyps in five siblings reported to have co-occurrence with a pathogenic MUTYH founder mutation, which was confirmed to be in trans through familial testing (Tsai GJ et al. Genet. Med. 2019 06;21:1435-1442). This variant has also been identified likely in trans with a MUTYH likely pathogenic or pathogenic variant in multiple individuals with clinical features of MUTYH-associated polyposis (Ambry internal data). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (Ambry internal data; Guan Y et al. Nat. Struct. Biol. 1998 Dec;5:1058-64; Manuel RC et al. J. Biol. Chem. 2004 Nov;279:46930-9). Of note, this variant is also designated as V220M in published literature. This amino acid position is not well 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.

Variant summary: MUTYH c.700G>A (p.Val234Met) results in a conservative amino acid change located in the HhH-GPD domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 250668 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (7.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.700G>A has been reported in the literature in individuals affected with Lynch syndrome, or pancreatic cancer (e.g. Fleischmann 2004, Peterlongo 2006, Yurgelun 2015, Dudley_2018). In one family with colon cancer, six affected siblings carry this variant and another pathogenic MUTYH variant (c.536A>G/p.Y179C). These data indicate that the variant is likely to be associated with disease in recessive pattern. One functional study in which the variant was expressed in MutY-disrupted Escherichia coli showed the variant to be partially defective, resulting in 2-fold higher spontaneous mutation rates compared to WT (Komine 2015). However, using human cells, a second functional study found the variant to have almost completely retained repair activity (Shinmura 2016). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic n=4, VUS n=6). Based on the evidence outlined above, the variant was classified as VUS possibly pathogenic.

The p.Val234Met variant in MUTYH has been reported in at least 3 individuals with colorectal cancer (Fleischmann 2004 PMID: 14991577, Peterlongo 2006 PMID: 16774938, Tsai 2019 PMID: 30374176). In one family, the variant was identified in trans with the pathogenic p.Tyr179Cys variant and these variants segregated in 4 affected siblings who had colon cancer or polyposis (Tsai 2019 PMID: 30374176). Furthermore, this variant has also been reported by one clinical laboratory in ClinVar in an individual with a personal and family history of colon cancer who also harbored a pathogenic MUTYH frameshift variant (ClinVar variation ID 135989, SCV001159672.1). In vitro functional studies are contradictory with one study providing evidence that the p.Val234Met variant may impact protein function (Komine 2015, PMID: 25820570), while another study showed that the protein function is fully retained (Shinmura 2016, PMID: 26694661). However, these types of assays may not accurately represent biological function. This variant has been identified in 0.01% (23/128662) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PM3, PM2_Supporting, PP1_Moderate.

The MUTYH c.700G>A (p.Val234Met) variant has been reported in the published literature in individuals affected with Lynch syndrome-associated cancers and/or polyps (PMID: 16774938 (2006), 14991577 (2004), 25980754 (2015), 28944238 (2017), 31422818 (2019), 33436027 (2021)), breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)), endometrial cancer (PMID: 36744932 (2023)) and hematological malignancies (PMID: 33850299 (2021)). This variant has also been observed in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). This variant was determined to segregate with disease in five siblings, each of whom were also positive for a known MUTYH pathogenic variant (c.536A>G, p.Tyr179Cys) and a documented history of colon cancer and/or over 20 colonic polyps (PMID: 30374176 (2019)). Functional studies examining the effect of this variant on MUTYH protein function have yielded conflicting results (PMID: 25820570 (2015), 26694661 (2016)). The frequency of this variant in the general population, 0.00018 (23/128662 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.