ClinVar Genomic variation as it relates to human health

This variant is denoted MUTYH c.1430C>A at the cDNA level, p.Thr477Lys (T477K) at the protein level, and results in the change of a Threonine to a Lysine (ACG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Thr477Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. MUTYH Thr477Lys occurs at a position that is conserved across species and is located within the NUDIX domain (Ruggieri 2013, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MUTYH Thr477Lys is pathogenic or benign. 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.

This missense variant replaces threonine with lysine at codon 477 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282890 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 threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 477 of the MUTYH protein (p.Thr477Lys). This variant is present in population databases (rs767747402, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 418800). 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.T477K variant (also known as c.1430C>A), located in coding exon 14 of the MUTYH gene, results from a C to A substitution at nucleotide position 1430. The threonine at codon 477 is replaced by lysine, an amino acid with similar properties. 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.