Genetic risk assessment for hereditary colorectal cancer and polyposis: updates and clinical implications

Identification of hereditary colorectal cancer (CRC) predisposition prompts important healthcare considerations for affected individuals and at-risk relatives. Approximately 5–10% of CRC cases are attributable to known hereditary syndromes, with higher prevalence among early-onset cases. Lynch syndrome remains the most common cause, while adenomatous and hamartomatous polyposis syndromes account for additional sources of hereditary CRC risk. Given overlapping phenotypes across syndromes, multi-gene panel testing (MGPT) is essential to establish accurate molecular diagnoses and guide risk stratification, surveillance, and risk-reduction strategies. This narrative review summarizes hereditary CRC and polyposis syndromes, current and emerging strategies for genetic testing, and evolving models of care delivery. Indications for genetic evaluation are outlined based on personal and family history, tumor molecular features, and polyp burden, along with consideration of universal genetic testing in CRC. Emerging diagnostic approaches, such as RNA analysis, assessment of constitutional MLH1 hypermethylation, and evaluation for mosaicism, are introduced as potential options for improved diagnostic yield in patients with unexplained but suggestive clinical presentations. Interpretation of genetic test results is discussed with emphasis on the substantive impact of cascade testing in relatives. Finally, alternative genetic service delivery models, including point-of-care and mainstreaming approaches, are introduced as potential means of enhancing access and scalability of cancer genetics services.