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Biallelic germline variants in MCM8 have been observed in a male patient with early-onset Lynch-like colorectal cancer and fertility problems, suggesting a recessive CRC predisposition gene (PMID:32841224). In a cohort of 16 mismatch repair–deficient CRC cases lacking germline mutations in MLH1, MSH2, MSH6, PMS2 or EPCAM and without MLH1 promoter methylation, two potentially pathogenic MCM8 variants were identified in one individual, and replication in an independent familial cancer cohort detected additional carriers without documented segregation.
Functional assays using CRISPR/Cas9-engineered MCM8 knockout cells and variant-specific mutagenesis demonstrated increased DNA damage, microsatellite instability and mutational signatures consistent with mismatch repair deficiency, supporting a loss-of-function mechanism in homologous recombination repair and MMR pathway engagement.
Key take-home: While biallelic MCM8 variants may underlie a subset of early-onset MMR-deficient CRC, additional segregation and variant‐specific data are required before incorporation into diagnostic testing.
Gene–Disease AssociationLimitedSingle recessive case with supportive functional data and unsegregated replication carriers. Genetic EvidenceLimitedOne proband with biallelic variants; replication carriers detected without segregation data. Functional EvidenceModerateCRISPR/Cas9 knockout and variant models showed DNA damage, microsatellite instability and MMR-like mutational signatures. |