VHL and neoplasm: VHLS is caused by germline mutation in the VHL tumor suppressor gene, which is localized on 3p and is inactivated in the tumor according to the Knudson two-hit model: one allele harbors germline “loss of function” mutation and the second allele acquires alteration in tumor cells due to somatic point mutation, large deletion (“loss of heterozygosity”), or promoter methylation.