Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000219128 | SCV000278457 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-06-30 | criteria provided, single submitter | clinical testing | The p.K491* variant (also known as c.1471A>T), located in coding exon 14 of the MUTYH gene, results from an A to T substitution at nucleotide position 1471. This changes the amino acid from a lysine to a stop codon within coding exon 14. This alteration occurs at the 3' terminus of theMUTYH gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 59 amino acids of the protein. However, premature stop codons are typically deleterious in nature, a significant portion of the protein is affected, and the impacted region is critical for protein function (Ambry internal data). Internal 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV001386175 | SCV001586313 | pathogenic | Familial adenomatous polyposis 2 | 2022-07-19 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Lys491*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 233982). 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). |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003477769 | SCV004222077 | likely pathogenic | not provided | 2023-09-16 | criteria provided, single submitter | clinical testing | This variant is predicted to cause the premature termination of MUTYH protein synthesis. This variant has not been reported in individuals with MUTYH related conditions. However, this variant has been reported in a carrier screening study (PMID: 29754767 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. |