A good example for investigating variants associated with reduced penetrance is the gene TP53 (HGNC:11998), in which pathogenic germline variants cause Li-Fraumeni syndrome (LFS) (MONDO:0018875), characterized by increased risk of various cancers, including the LFS core cancers such as early-onset breast cancer, brain cancer, adrenocortical carcinoma, and sarcomas.7 This evidence concerns the gene TP53 and Li-Fraumeni syndrome.