ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1501C>T (p.Gln501Ter) (rs932830392)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000760568 SCV000890459 likely pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing 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.
Color Health, Inc RCV000777365 SCV000913227 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000777365 SCV001172299 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-28 criteria provided, single submitter clinical testing 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.
Invitae RCV001378375 SCV001575927 likely pathogenic MYH-associated polyposis 2020-05-03 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MUTYH gene (p.Gln501*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acids of the MUTYH protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 620207). This variant disrupts the conserved PCNA binding motif of MUTYH (Gln526-Phe533, also known as Gln512-Phe519 in the literature because of transcript nomenclature differences), which has been shown to be critical for MUTYH-PCNA binding (PMID: 11092888, 26377631). Experimental studies have shown that MUTYH and PCNA co-localize at sites of DNA replication, and that MUTYH-PCNA complexes possess adenine glycosylase activity (PMID: 11433026). In MUTYH-deficient murine cells, a mutated MUTYH protein in which the conserved PCNA binding motif was disrupted did not increase repair efficiency as compared to wild-type MUTYH (PMID: 11864576). 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.

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