ClinVar Genomic variation as it relates to human health

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 479 of the MUTYH protein (p.Glu479Lys). This variant is present in population databases (rs376790729, gnomAD 0.008%). This missense change has been observed in individual(s) with multiple colon adenomas (PMID: 20618354). ClinVar contains an entry for this variant (Variation ID: 186129). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

Observed without a second MUTYH variant two related individuals with multiple adenomas and in an individual with soft tissue sarcoma (Morak et al., 2010; Ballinger et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as Glu476Lys; This variant is associated with the following publications: (PMID: 27498913, 20618354, 23108399)

This missense variant replaces glutamic acid with lysine at codon 479 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 identified as a heterozygous variant in two related individuals affected with polyposis (PMID: 20618354) and an individual affected with colorectal cancer (PMID: 21901162). In a large international case-control meta-analysis, this variant was reported in 1/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 11/282904 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 glutamic acid with lysine at codon 479 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 identified as a heterozygous variant in two related individuals affected with polyposis (PMID: 20618354) and an individual affected with colorectal cancer (PMID: 21901162). In a large international case-control meta-analysis, this variant was reported in 1/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 11/282904 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.

The p.E479K variant (also known as c.1435G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide position 1435. The glutamic acid at codon 479 is replaced by lysine, an amino acid with similar properties. This alteration was found in an individual with 10 to 100 adenomas at age 41 and also in her daughter, who was affected with 20 to 30 adenomas first diagnosed in her teens. A second MUTYH alteration was not identified in this patient (Morak M et al. Clin. Genet. 2010 Oct;78:353-63). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). Of note, this alteration is also known as c.1393G>A (p.Glu465Lys) in published literature. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Variant summary: MUTYH c.1435G>A (p.Glu479Lys) results in a conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251492 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1435G>A has been reported in the literature in at least one heterozygous individual affected with an attenuated familial adenomatous polyposis III colorectal neoplasia (e.g. Morak_2010). This report does not provide sufficient evidence to allow 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: 34130653, 20618354). ClinVar contains an entry for this variant (Variation ID: 186129). Based on the evidence outlined above, the variant was classified as uncertain significance.