ClinVar Genomic variation as it relates to human health

Variant summary: MUTYH c.1588G>T (p.Asp530Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251494 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (6.8e-05 vs 0.0046), allowing no conclusion about variant significance. c.1588G>T has been reported in the literature in an individual affected lung adenocarcinoma (Barreiro_2022) and as a VUS in a setting of multigene panel testing in an individual with pancreatic ductal adenocarcinoma (PDAC) who did not meet the criteria for familial pancreatic cancer (FPC) or the NCCN criteria (Cremin_2020). 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. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces aspartic acid with tyrosine at codon 530 of the MUTYH protein. This variant is also known as c.1546G>T (p.Asp516Tyr) based on an alternative transcript (NM_001048171). 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 an individual affected with pancreatic ductal adenocarcinoma (PMID: 32255556), melanoma (PMID: 29641532), and breast cancer (PMID: 33471991), but also in unaffected controls (PMID: 30267214, 33471991). This variant has been identified in 19/282892 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.

Reported in an individual with melanoma, breast, and endometrial cancer as well as an individual with pancreatic cancer (PMID: 32255556, 29641532); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26246501, 29641532, 32255556, 11092888, 23108399, 16996809, 30267214, 33471991, 34816434)

The p.D530Y variant (also known as c.1588G>T), located in coding exon 16 of the MUTYH gene, results from a G to T substitution at nucleotide position 1588. The aspartic acid at codon 530 is replaced by tyrosine, an amino acid with highly dissimilar properties. In one study, this variant was not detected in 165 colorectal cancer and/or polyposis patients and was identified in 2/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum. Genet., 2018 Oct;137:795-806). This amino acid position is highly 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.

The MUTYH c.1588G>T (p.Asp530Tyr) variant has been reported in the published literature in individuals with pancreatic cancer (PMID: 32255556 (2020)), melanoma and breast cancer (PMID: 29641532 (2018)), and lung adenocarcinoma (PMID: 34816434 (2022)). In a large breast cancer association study, this variant was reported both in healthy individuals and those with breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). The frequency of this variant in the general population, 0.00013 (17/129190 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 530 of the MUTYH protein (p.Asp530Tyr). This variant is present in population databases (rs147923905, gnomAD 0.01%). This missense change has been observed in individual(s) with pancreatic cancer and/or lung cancer (PMID: 32255556, 34816434). ClinVar contains an entry for this variant (Variation ID: 182685). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.

This missense variant replaces aspartic acid with tyrosine at codon 530 of the MUTYH protein. This variant is also known as c.1546G>T (p.Asp516Tyr) based on an alternative transcript (NM_001048171). 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 an individual affected with pancreatic ductal adenocarcinoma (PMID: 32255556), melanoma (PMID: 29641532), and breast cancer (PMID: 33471991), but also in unaffected controls (PMID: 30267214, 33471991). This variant has been identified in 19/282892 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 MUTYH c.1588G>T variant is predicted to result in the amino acid substitution p.Asp530Tyr. This variant was reported in an individual with pancreatic ductal adenocarcinoma and in an individual with lung adenocarcinoma (Table S3, Cremin et al. 2020. PubMed ID: 32255556; Barreiro RAS et al. 2021. PubMed ID: 34816434). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/182685/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.