In Vivo and in Vitro Characterization of a Novel Germline RET Mutation Associated with Low-Penetrant Nonaggressive Familial Medullary Thyroid Carcinoma

Context: RET mutation analysis provides useful information on the clinical outcome of medullary thyroid carcinomas (MTCs) and the risk of disease in the family members. Objective: The objective of this study was to document genotype-phenotype relationships in an Italian family with a novel RET mutation. Design/Setting: RET gene alterations were investigated in a patient with unifocal MTC and her relatives. The identified mutation was subjected to in vitro functional testing. Patients: Patients included a female proband who developed MTC at age 60, her five children, and three grandchildren. Main Outcome Measures: DNA extracted from the blood and the proband’s tumor were analyzed for RET alterations. The transforming potential and mitogenic properties of the identified mutation were investigated. Results: A novel heterozygous germline RET mutation at codon 777 (AAC→AGC, N→S) (RET/N777S) was identified in the proband and three of her relatives. Two of the latter presented thyroid nodules, but none had MTC o...