The RET protooncogene was originally identified in 1985. It encodes for a receptor tyrosine kinase. The RET receptor is activated by its ligand glial cell-derived neurotrophic factor. A polymorphism, RETp (G691S), in the intracellular juxtamembrane domain of RET, which enhances signaling by glial cell-derived neurotrophic factor has been described and studied previously in pancreatic cancer, medullary thyroid cancer, the multiple endocrine neoplasia 2 syndromes, and recently in cutaneous malignant melanoma. In particular, it has been shown that desmoplastic melanomas, which have neurotrophic features, have a high frequency of this polymorphism. In previous studies, however, it was not clear whether this was a germline or somatic change. Previous studies on pancreatic cancer indicated that both mechanisms may occur. To clarify this further we examined peripheral blood cell DNA from 30 patients with desmoplastic melanomas and 30 patients with nondesmoplastic melanoma for the RETp. In this study, a germline polymorphism was found in 30% of the patients with desmoplastic melanomas and 21% of the patients with nondesmoplastic melanoma. These findings indicate that the RETp may be a genetic risk factor for the development of desmoplastic melanoma.