ClinVar Genomic variation as it relates to human health

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Variant summary: MUTYH c.1255G>A (p.Ala419Thr) results in a non-conservative amino acid change located in the C-terminal domain (IPR029119) and NUDIX hydrolase domains (IPR000086) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251158 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (6.4e-05 vs 0.0046), allowing no conclusion about variant significance. To our knowledge, there are no reports of c.1255G>A in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating an impact on protein function in the literature. c.1255G>A has been reported in an individual with Lynch syndrome (Yurgelun_2015) and in an individual with glioblastoma mulitforme (Lu_2015). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. Eight other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with Lynch-associated cancers and/or polyps, breast cancer, or glioblastoma, and also observed in control groups (PMID: 26689913, 33471991, 25980754); This variant is associated with the following publications: (PMID: 25980754, 19725997, 17581577, 17161978, 26689913, 33122805, 33471991, 23108399)

This missense variant replaces alanine with threonine at codon 419 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with MUTYH-associated polyposis, colorectal cancer, glioblastoma, and suspected Lynch syndrome (PMID: 17581577, 25980754, 26689913, Insight-database.org), This variant has been identified in 19/282560 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This missense variant replaces alanine with threonine at codon 419 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with MUTYH-associated polyposis, colorectal cancer, glioblastoma, and suspected Lynch syndrome (PMID: 17581577, 25980754, 26689913, Insight-database.org), This variant has been identified in 19/282560 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.