Balancing benefits, costs, and harms: policy implications of expanding cancer susceptibility testing from genetics clinics to the general population.

Cancer susceptibility testing is rapidly advancing beyond specialist genetics clinics into routine oncology and population-level genomics initiatives. This expansion positions germline pathogenic variants in cancer susceptibility genes and polygenic risk scores as crucial tools for precision prevention, surveillance, and early detection. However, implementation has outpaced the evidence needed to justify testing at scale, particularly in well populations. For a small number of first-wave genes-including BRCA1, BRCA2, MLH1, and MSH2-cancer risks are well established and downstream medical interventions are supported by substantial observational evidence, albeit with an absence of randomised trials. Contrastingly, for many later discovered genes now included on multigene panels, penetrance estimates remain uncertain, variant-specific risks are poorly resolved, and evidence is scarce or absent regarding mortality reduction, quality of life benefit, or cost-effectiveness for the recommended downstream interventions. Polygenic risk scores offer promise for stratified prevention, but their discriminatory capacity is constrained, performance is ancestry dependent, and clinical utility remains uncertain in most settings. Building on the Lancet Oncology Commission on cancer genomics and precision oncology, this Policy Review examines the evidentiary, clinical, and health-system challenges associated with cancer susceptibility testing across clinical care and public health prevention. We argue that the value of such testing should be assessed in terms of its clinical value and public health utility, with careful attention to the context in which testing is offered. We propose a tiered, context-specific approach to implementation, aimed at distinguishing settings in which susceptibility testing could provide a net benefit from those scenarios in which its use should remain restricted, highly selective, or confined to research.