ClinVar Genomic variation as it relates to human health

Variant summary: MUTYH c.679G>A (p.Ala227Thr) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251330 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.679G>A has been reported in the literature in a cohort of individuals undergoing testing for genes implicated in hereditary cancer predisposition (Tsaousis_2019)and also as a somatic variant (vandeWetering_2015). These reports 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. Seven 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 missense variant replaces alanine with threonine at codon 227 of the MUTYH protein. This variant is also known as c.637G>A (p.Ala213Thr) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been observed in individuals affected with MUTYH-associated polyposis but has been observed in individuals with breast and/or ovarian cancer (PMID: 26689913, 31159747, 36035419). This variant has been identified in 9/251330 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 sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 227 of the MUTYH protein (p.Ala227Thr). This variant is present in population databases (rs369854269, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 26689913, 31159747, 31465090). ClinVar contains an entry for this variant (Variation ID: 229778). 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. 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.

The p.A227T variant (also known as c.679G>A), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 679. The alanine at codon 227 is replaced by threonine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with breast cancer (Stuttgen K et al. JAMA Oncol, 2019 Oct;5:1506-1508). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.319G>A p.Ala107Thr; c.595G>A p.Ala199Thr; This variant is associated with the following publications: (PMID: 15673720, 25957691, 26689913, 24463508, 31159747, 31937788, 31465090, 33471991, 36035419, 37937776, 36243179)

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.

This missense variant replaces alanine with threonine at codon 227 of the MUTYH protein. This variant is also known as c.637G>A (p.Ala213Thr) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been observed in individuals affected with MUTYH-associated polyposis but has been observed in individuals with breast and/or ovarian cancer (PMID: 26689913, 31159747, 36035419). This variant has been identified in 9/251330 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.