Purpose Melanoma, the deadliest form of skin cancer, has a concerning 70-87% increased incidence among DoD aircrew compared to the general population and DoD non-flyers (after adjusting for age, sex, and race/ethnicity). DoD warfighters, including pilots, aircrew, groundcrew, sailors, marines, and soldiers, face unique occupational exposures (e.g. UV, radiation, circadian disruption, stress, chemicals) that elevate their cancer and melanoma risks. While environmental factors are known contributors, the interplay between genetic predisposition, specifically through cancer predisposition genes (CPGs), and occupational exposures remains poorly understood, hindering precision prevention. This study aims to elucidate the critical role of melanoma CPGs in disease progression, particularly metastasis, to inform personalized healthcare strategies that enhance force health protection and medical readiness across the DoD. Methods Leveraging large-scale genomic data from the NIH All of Us database (~250,000 participants) and National Cance Institute’s The Cancer Genome Atlas (TCGA) (1,849 melanoma patients), we systematically analyzed the frequency of pathogenic variants in 23 key melanoma CPGs. We then determined the impact of these CPGs on the metastatic potential of melanoma using bioinformatic tools, including Integrative Genomics Viewer. Chi-squared tests were applied for statistical analysis of metastasis site percentage values derived from TCGA data. Results Our analysis identified prevalent pathogenic or likely pathogenic variants in key CPGs such as BRCA1, ATM, CDKN2A, ERCC2, CHEK2, TERT, and TP53 within the American population. Crucially, we discovered strong associations between specific mutations in TERT, CDKN2A, ATM, and MITF with the number of cases having advanced melanoma metastasis. Notably, TERT mutations correlated with an 1100% increase in metastasis, and specific CDKN2A mutations were associated with a 120% elevation in the number of metastatic cases. These findings underscore the profound impact of genetic variants on melanoma's aggressive progression. Conclusion This study underscores the critical role of melanoma CPGs in advancing cancer prevention and management. All DoD Service branches face melanoma survival rates of 99% for localized melanoma cases but only 35% for metastasized cases. Our findings provide foundational evidence for implementing genetic testing to enable risk-stratified melanoma screening and targeted early interventions. Such proactive, genomic-informed strategies are essential for preserving the health and readiness of high-value military personnel and align directly with the Defense Health Agency's mission to optimize health outcomes, improve force health protection, and ensure a medically ready force. Further research is imperative to ascertain the prevalence of these variants within military occupational cohorts and to translate these crucial genomic insights into actionable, interoperable clinical guidelines throughout the DoD. Disclaimer The views expressed in this presentation reflect the results of research conducted by the author(s) and do not necessarily reflect the official policy or position of the Defense Health Agency, Department of Defense, nor the U.S. Government. The study protocol was approved by the 60 MDG Exemption Determination Official in compliance with all applicable Federal regulations governing the protection of human and animal subjects. Research data were derived from two approved 60 MDG Institutional Review Board protocol numbers FDG20230053R and FDG20240061R. This work has received a provisional patent under DHA. All authors have no conflicts to report.