The variable clinical phenotype, lack of tumor-based screening to triage CRC-affected patients for MUTYH gene testing (akin to MMR immunohistochemistry for Lynch syndrome), conflicting reports regarding CRC risks in monoallelic MUTYH carriers, and the absence of validated functional assays for variant classification present important clinical challenges that limit effective identification and clinical management of MUTYH carriers. The gene discussed is MUTYH; the disease is Lynch syndrome.