ClinVar Genomic variation as it relates to human health

This variant is denoted MUTYH c.724G>A at the cDNA level, p.Val242Met (V242M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Val242Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. MUTYH Val242Met occurs at a position that is conserved across species and is located within the FeS cluster domain (Ruggieri 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MUTYH Val242Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.

The p.V242M variant (also known as c.724G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 724. The valine at codon 242 is replaced by methionine, an amino acid with highly similar properties. This alteration was identified in seven individuals with colorectal adenomas from Jordan (Mahasneh A et al. Iran Biomed J. 2019 11;23:412-22). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 242 of the MUTYH protein (p.Val242Met). This variant is present in population databases (rs769766446, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of MUTYH-associated polyposis (PMID: 31104418, 34326862). ClinVar contains an entry for this variant (Variation ID: 233587). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Probably Damaging". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: MUTYH c.724G>A (p.Val242Met) results in a conservative amino acid change located in the HhH-GPD superfamily base excision DNA repair protein domain (PF00730) 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 8e-06 in 250450 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.724G>A has been reported in the literature in individuals affected with colorectal adenoma (examples: Mahasneh_2019, Bhai_2021). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 31104418). ClinVar contains an entry for this variant (Variation ID: 233587). Based on the evidence outlined above, the variant was classified as uncertain significance.

The MUTYH c.724G>A variant is predicted to result in the amino acid substitution p.Val242Met. This variant was reported in an individual with solitary colorectal cancer and in an individual with colorectal polyps (Supplementary Data 5. Cereda M et al 2016. PubMed ID: 27377421; Table S4. Bhai et al. 2021. PubMed ID: 34326862). This variant was also reported in seven individuals with colorectal adenoma (Mahasneh et al 2019. PubMed ID: 31104418). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/233587/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.