The neurofibromatosis 1 (EIF 7) gene product, neurofibromin, contains a GTPase-activating protein (GAP)-related domain, or NFl GRD, that is able to downregulate~ 21’“~ by stimulating its intrinsic GTPase. Since p21m. GTP is a major regulator of growth and differentiation, mutant neurofibromins resulting from somatic mutations in the NF1 gene might interfere with ras signaling pathways and contribute to the development of tumors. We describe an amino acid substitution in the NFl GRD, altering Lys-1423, that has occurred in three tumor types: colon adenocarcinoma, myelodysplastic syndrome, and anaplastic astrocytome, and in one family with neurofibromatosis 1. The GAP activity of the mutant NFl GRD is 200-to 400-fold lower than that of wild type, whereas binding affinity is unaffected. Thus, germline mutations in NF7 that cause neuroflbromatosis 1 can also occur in somatic cells and contribute to the development of sporadic tumors, including tumors not associated with neurofibromatosis 1.