Cancer Genetic Predisposition and Clinical Applications-A Narrative Review on Germline Genetic Testing, High-Risk Cancer Surveillance and Management.

Understanding germline genetic variation is essential for improving human cancer care. Cancer predisposition genetic testing has become a part of the landscape of healthcare. Clinical guidelines have been established to identify individuals with monogenic risk, support variant classification, and guide enhanced cancer surveillance and prevention strategies. However, genetic mechanisms, cancer syndromes, genetic testing, patient education, and high-risk cancer management are often addressed in separate professional domains leading to limited cross-disciplinary understanding and confusion. A review tailored to a broad spectrum of clinicians is necessary to synthesize information, connect key concepts, and clearly define the principles and reasoning underlying recommended practice. Advanced genetic technology identified numerous genes and countless pathogenic variants contributing to a wide range of cancer predispositions. Rapid and accurate next-generation sequencing has enabled the routine use of multi-gene panel testing to stratify cancer risk. In precision cancer therapies, tumor genomic profiling frequently uncovers not only somatic alterations but also germline mutations, revealing additional cancer risk for the patients and their biological relatives. Beyond monogenic risks, the cumulative effect of numerous common polygenic factors can also significantly influence cancer susceptibility. Despite major advances in integrating germline genetic information into cancer care, substantial challenges remain in variant interpretation, precise risk stratification, and implementing personalized screening and prevention strategies. Using several cancer predisposition syndromes as examples, such as breast and ovarian cancer syndrome, Lynch syndrome, and Li-Fraumeni syndrome, the review provides a high-level overview of key concepts, the evolution of knowledge and technology, and the rationale underlying the current clinical management strategies.