TP53 and cancer: Selection of individuals presenting phenotypes of extremely high cancer risk may facilitate the identification of these variants, as seen with pathogenic variants in TP53 and BRCA, discovered through the study of individuals presenting early-onset cancer and familial aggregation.29, 30, 31 Of note, most known high-risk cancer variants have been discovered through association with familial aggregation, while our strategy assesses high-risk cancer variants outside this framework.