Multi-Gene panel-based genetic testing has emerged as the standard of care for cancer genetic testing. This has led to the identification of TP53 mutations among individuals without classic personal or family histories of Li-Fraumeni syndrome. These mutations may be due to mosaicism, clonal hematopoiesis, or due to form fruste Li-Fraumeni syndrome. We will discuss how these findings are shaping clinical cancer genetics care and how they are leading to a re-evaluation of the epidemiology and penetrance of germline TP53 mutations.