PROJECT SUMMARY/ABSTRACT Preventive genomic medicine, particularly identification of individuals with inherited cancer risk, provides health systems with the opportunity to improve longevity and quality of life for their patients. The ability to uncover substantially elevated risk of disease through genomic testing, act to reduce that risk, and improve outcomes while lowering costs has been the longstanding promise of genomic medicine. In the case of inherited cancer, however, adherence to recommended risk management following genomic testing is low. Further, our pilot data suggests that health systems are reluctant to expand cancer genomic testing without a clearer idea of how to manage tested patients over time. Our goal in this application is to address this roadblock to genomic medicine implementation. Specifically, we will demonstrate the benefits that adopting population management interventions following genomic testing can provide health systems, using hereditary cancer as a case example. We will revise and rigorously evaluate two population management interventions (web resources and personalized outreach) that improve timely patient outreach and end-to-end tracking without burdening providers. Web resources is a low-touch intervention that links patients with existing educational resources (e.g., the Facing Our Risk of Cancer Empowered website). Personalized outreach is a high-touch intervention that connects patients with a dedicated care manager to discuss risk management and provide care reminders. Both interventions are highly scalable and mirror population management programs that health systems have used to support cancer screening, diabetes management, and other evidence-based care for decades. We will compare web resources and personalized outreach to usual care in a pragmatic hybrid type-1 randomized trial that engages patients captured in hereditary cancer registries within two health systems, Kaiser Permanente Northwest (KPNW) and Denver Health (DH). KPNW is a vertically integrated health system and DH is a federally qualified health center, providing two highly unique evaluation settings. Our primary effectiveness outcome is the proportion of registry patients up to date with recommended cancer screening over two years. We will collect secondary implementation outcomes, including the acceptability, appropriateness, feasibility, sustainability, and costs of high- and low-touch intervention approaches. By providing clinical champions with essential data and tools to select and implement population management interventions that address critical gaps in post-testing quality and patient safety, this innovative project will advance preventive genomic medicine.