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Yet genetic mechanisms, cancer syndromes, testing workflows, patient education, and high-risk management are often taught in separate domains, limiting cross-disciplinary clarity. This narrative review synthesizes key concepts, technology evolution, and the clinical rationale for current practice. 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High-Risk Cancer Surveillance and Management  \nXia Wang   \nAcademic Editor: GokceA. Toruner  \nReceived: 26 January 2026  \nRevised: 28 April 2026  \nAccepted: 6 May 2026  \nPublished: 31 May 2026  \nCopyright: © 2026 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \nCollege of Medicine, Central Michigan University, Mt. Pleasant, MI 48601, USA; [wang23x@cmich.edu](wang23x@cmich.edu); Tel.: +1-(989)746-7500  \nAbstract  \nUnderstanding 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.  \nKeywords: cancer genetics; tumor suppressor gene; germline genetic testing; variant classification; cancer predisposition; hereditary cancer syndrome; high-risk cancer screening; cancer prevention; polygenic risk score (PRS)  \n1. Introduction  \nGermline genetic variation contributes significantly to tumorigenesis, tumor progression, and therapeutic response in cancer. Approximately 8% of cancers have monogenic etiologies [1] . Over the past decades, substantial advances have been made in leveraging germline information to improve cancer care. Numerous high and moderate-penetrance variants, particularly in tumor suppressor genes, have been identified as drivers of inherited  \ncancer susceptibility. Therefore, clinical genetic testing for monogenic pathogenic variants (mutations) has been widely adopted in risk-stratified cancer screening and prevention.  \nHowever, hereditary cancer syndromes, genetic testing, testing candidate identification, patient education, and high-risk cancer management are often addressed in separate professional domains, leading to siloed education and limited cross-disciplinary understanding. Consequently, specialists in one area may lack comprehensive familiarity with related fields. Identifying high-risk individuals and initiating the evaluation process relies on a broad range of clinicians. This review aim","cbCaipLBZasWfw0H","https://ap.wps.com/l/cbCaipLBZasWfw0H","pdf",346220,24,"English","# Introduction\n## Clinical impact of germline genetic variation\n## Hereditary cancer syndromes and interdisciplinary gaps\n## Review scope and timeline\n# Clinical guidelines and cancer–gene management\n## Guideline development and updating\n## Evidence limits for trials","[{\"question\":\"What is the clinical purpose of germline genetic testing in cancer predisposition?\",\"answer\":\"It helps identify individuals with monogenic risk, supports variant classification, and guides enhanced surveillance and prevention strategies.\"},{\"question\":\"Why does the review emphasize cross-disciplinary understanding?\",\"answer\":\"Genetic mechanisms, syndromes, testing, patient education, and high-risk management are often handled in separate professional domains, which can create siloed knowledge and confusion.\"},{\"question\":\"How has next-generation sequencing changed cancer predisposition testing?\",\"answer\":\"Rapid, accurate next-generation sequencing enables routine multi-gene panel testing to stratify cancer risk and improves integration of germline findings into cancer care.\"}]","Cancer Genetic Predisposition and Clinical Applications - A Narrative Review on Germline Genetic Testing - High-Risk Cancer Surveillance and Management | PDF",1790140847]