ClinVar Genomic variation as it relates to human health

In the published literature, this variant has been reported in affected individuals with colorectal cancer (PMID: 28135145 (2017) and 34326862 (2021)) and in an individual with hereditary mixed polyposis syndrome who also had a pathogenic GREM1 duplication (PMID: 26947005 (2016)). It has also been reported in individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)), as well as in controls (PMIDs: 30267214 (2018) and 33471991 (2021)). The frequency of this variant in the general population, 0.00014 (18/129178 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 465 of the MUTYH protein (p.Pro465Ala). This variant is present in population databases (rs375597447, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). This variant is also known as c.1351C>G (p.P451A). ClinVar contains an entry for this variant (Variation ID: 141925). 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 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.

This missense variant replaces proline with alanine at codon 465 of the MUTYH protein. This variant is also known as c.1351C>G (p.Pro451Ala) 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 colorectal cancer (PMID: 28135145) and in a family affected with hereditary polyposis, where the disease segregated with a pathogenic duplication of the GREM1 gene enhancer region (PMID: 26947005). This variant has been identified in 19/282872 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.P465A variant (also known as c.1393C>G), located in coding exon 14 of the MUTYH gene, results from a C to G substitution at nucleotide position 1393. The proline at codon 465 is replaced by alanine, an amino acid with highly similar properties. This alteration was reported as a variant of uncertain significance identified in a cohort of 1058 colorectal cancer patients who underwent multi-gene panel testing and were unselected for age of diagnosis, family history, or MSI/MMR status (Yurgelun MB et al J. Clin. Oncol. 2017 Apr;35:1086-1095). This variant was also detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Reported in the heterozygous state in individuals with colorectal cancer or polyposis; however, a pathogenic duplication in SCG5/GREM1 was also identified in the polyposis case (PMID: 26947005, 28135145); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(Pro451Ala); This variant is associated with the following publications: (PMID: 28135145, 26947005, 23108399, 34326862, 37937776)

This missense variant replaces proline with alanine at codon 465 of the MUTYH protein. This variant is also known as c.1351C>G (p.Pro451Ala) 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 colorectal cancer (PMID: 28135145) and in a family affected with hereditary polyposis, where the disease segregated with a pathogenic duplication of the GREM1 gene enhancer region (PMID: 26947005). This variant has been identified in 19/282872 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.

Variant summary: MUTYH c.1393C>G (p.Pro465Ala) results in a non-conservative amino acid change located in the MutY, C-terminal domain (IPR029119) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251494 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (6.8e-05 vs 0.0046), allowing no conclusion about variant significance. c.1393C>G has been reported in the literature in individuals affected with colorectal cancer and/or polyposis, and breast cancer (Ziai_2016, Yurgelun_2017, Bhai_2021). In one of these reports this MUTYH variant was not the cause of disease as a different pathogenic variant, namely a 40 kb duplication upstream of the GREM1 gene segregated with the hereditary mixed polyposis syndrome (HMPS) phenotype (Ziai_2016). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 28135145, 26947005). ClinVar contains an entry for this variant (Variation ID: 141925). Based on the evidence outlined above, the variant was classified as uncertain significance.

The MUTYH p.Pro465Ala variant was not identified in the literature, nor was it identified in dbSNP, HGMD, “InSiGHT Colon Cancer Database”, or the COSMIC database. The variant was identified in the NHLBI Exome Sequencing Project, with a frequency of 0.0001 in European American alleles; however, this frequency is based on one occurrence of the variant allele in 8600 alleles tested. The p.Pro465 residue is conserved in mammals but not across lower organisms, and the variant amino acid Alanine (Ala) is present in chicken, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.