ClinVar Genomic variation as it relates to human health

This variant is denoted MUTYH c.1501C>T at the cDNA level and p.Gln501Ter (Q501X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through protein truncation. Even though this frameshift occurs near the end of the gene in the second to last exon, and nonsense-mediated decay is not expected to occur, it is significant since the last 49 amino acids are no longer translated. Furthermore, the truncation would disrupt the PCNA domain (Parker 2001, Ruggieri 2013). Although this variant has not, to our knowledge, been reported in the literature as a germline variant, it is considered likely pathogenic.

This variant changes 1 nucleotide in exon 15 of the MUTYH gene, creating a premature translation stop signal. While this variant is not expected to trigger nonsense-mediate decay, it is predicted to truncate the C-terminus of the protein that has been shown to be important for PCNA binding (PMID: 11092888). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the conserved PCNA binding motif of the MUTYH protein, which has been shown to be critical for MUTYH-PCNA binding and repair efficiency (PMID: 11092888, 26377631, 11433026, 11864576). While functional studies have not been performed to directly test the effect of this variant on MUTYH protein function, this suggests that disruption of this region of the protein is causative of disease. ClinVar contains an entry for this variant (Variation ID: 620207). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln501*) in the MUTYH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the MUTYH protein.

The p.Q501* variant (also known as c.1501C>T), located in coding exon 15 of the MUTYH gene, results from a C to T substitution at nucleotide position 1501. This changes the amino acid from a glutamine to a stop codon within coding exon 15. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of MUTYH, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 49 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural analysis suggests that this alteration is expected to result in loss of predicted and confirmed interaction and regulatory domains, including PCNA-binding Pip domain, which results in loss of DNA repair function in-vitro (Chang DY et al. J. Biol. Chem. 2002 Apr;277:11853-8). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.