Exceptions to this trend are genes that suffer germline variants that confer susceptibility to cancer, such as the von Hippel-Lindau syndrome caused by some variants in VHL; Cowden disease 5 caused by mutations in PIK3CA; Li-Fraumeni syndrome 1 and TP53; and proteins related to the RAS family, or belonging to RAS pathways, whose germline mutations produce developmental diseases that frequently increase the risk of cancer29. This evidence concerns the gene PIK3CA and von Hippel-Lindau disease.