Pathogenicity of DNA Variants and Double Mutations in Multiple Endocrine Neoplasia Type 2 and Von Hippel-Lindau Syndrome

Context: Cancer genetics is fundamental for preventive medicine, in particular in pheochromocytoma-associated syndromes. Variants in two susceptibility genes, SDHC and RET, were found in a kindred with head and neck paraganglioma. This observation of coincident DNA variants, both reported as pathogenic, in two known susceptibility genes prompted the question of their pathogenic relevance. Objective: Our objective was to elucidate the pathogenic role of the detected variants and study the prevalence of such variants. Patients: Patients were registrants from the European-American Pheochromocytoma-Paraganglioma and German von Hippel-Lindau Disease Registries. Design: Analysis of germline mutation screening results for all pheochromocytoma-paraganglioma susceptibility genes, including RET [multiple endocrine neoplasia type 2(MEN2)] and VHL [von Hippel-Lindau disease (VHL)]. Cases in which more than one DNA variant was found were clinically reevaluated, and cosegregation of the disease with the variant was analyzed within the registrants' families. A total of 1000 controls were screened for the presence of detected variants, and in silico analyses were performed. Results: Three variants were identified, RET p. Tyr791Phe and p.Ser649Leu and VHL p.Pro81Ser. The frequencies of RET p.Ser649Leu (0.07%) and p. Tyr791Phe (0.9%) compared with controls excluded the two variants' role in the etiology of MEN 2 and VHL. None of the carriers of the RET variants who underwent prophylactic thyroidectomy showed medullary thyroid carcinoma. Clinical reinvestigation of 18 variant carriers excluded MEN2. VHL variant p.Pro81Ser, also previously described as a mutation, did not segregate with the VHL in one family. In silico analyses for these variants predicted unmodified protein function. Conclusions: RET p. Tyr791Phe and p.Ser649Leu and VHL p.Pro81Ser are definitely not pathogenic mutations for VHL and MEN2. Misinterpretation results in irreversible clinical consequences. (J Clin Endocrinol Metab 95: 308-313, 2010)