VHL P25L is not a Pathogenic von Hippel-Lindau Mutation

Abstract

von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome in which affected individuals may develop CNS and retinal hemangioblastomas, pheochromocytomas, renal cell carcinoma, and cysts of various organs. The VHL gene has been localized to chromosome 3p25-26 and >500 germline mutations have been identified. A rare variant of the VHL gene results in the substitution of lysine for proline at position 25 (P25L) in the larger of the two VHL proteins. This VHL variant has previously been described in a limited number of cases and has been strongly suggested to be non-pathogenic, but this has not been proven. A family with a medical history suggestive of VHL disease was investigated using DNA sequence analysis to determine the presence of the P25L variant of the VHL protein. Sequence analysis identified the VHL P25L variant in 7 of 14 family members, one of whom had a single retinal hemangioma, which is in itself insufficient to diagnose VHL disease. The variant was not identified in a family member with clear cell renal carcinoma, which is a hallmark feature of VHL disease. On the basis of these results, it is concluded that P25L is a benign variant of the VHL protein and individuals carrying this variant should not be required to undergo screening for VHL manifestations.