TP53 and breast cancer: This scenario is plausible for breast cancer, as many breast cancer susceptibility variants identified from GWAS are protein-coding variants or directly regulate the expression of cancer genes (e.g., missense variant rs35383942 in PHLDA3, which encodes a p53-regulated repressor of Akt [40]), thus have effects on breast cancer development through other functional pathways that are not mediated by the acquirement of somatic mutations [41–44].