The VHL gene is a tumor suppressor gene located on chromosome 3, which usually controls cell growth and cell death. Both copies of a tumor suppressor gene must be altered, or mutated, before a person will develop cancer. In VHL, the first mutation is inherited from either the mother or the father and is therefore present in all cells of the body. This is called a germline mutation. Whether a person who has a germline mutation will develop a tumor and where the tumor(s) will develop depends upon where (which cell type) the second mutation occurs. For example, if the second mutation is in the retina, then a retinal hemangioblastoma may develop. If it is in the brain, then a hemangioblastoma may develop there. The process of tumor development actually requires mutations in multiple growth control genes. Loss of both copies VHL is just the first step in the process. What causes these additional mutations to be acquired is unknown. Possible causes include chemical, physical, or biological environmental exposures or chance errors in cell replication.
Some individuals who have inherited a germline VHL mutation never develop cancer because they never get the second mutation necessary to knock out the function of the gene and start the process of tumor formation. This can make the cancer appear to skip generations in a family, when, in reality, the mutation is present. Persons with a mutation, regardless of whether they develop cancer, however, have a 50/50 chance to pass the mutation on to the next generation. About 1-3% of VHL cases are new mutations, not inherited from a parent.
It is also important to remember that the VHL gene is not located on the sex chromosomes. Therefore, mutations can be inherited from either the mother or the father's side of the family.