Background: Patients with rearranged-during-transfection ( Methods: Thirty-six patients with a pathogenic variant in codon Y791F were analysed in this retrospective clinical and biochemical follow-up study in terms of their clinical manifestation. The patients were diagnosed within a prospective calcitonin screening program of individuals with thyroid nodules, PCC and/or PHPT. Results: MTC was diagnosed in three index cases of patients aged between 56 and 69 years. Beside thyroid nodules, neoplastic C-cell hyperplasia (nCCH) was diagnosed in five index cases, aged between 48 and 69 years. One index patient presented with unilateral PCC at the age of 68 years and another with PHPT at the age of 54 years. The patients were longitudinally monitored for a median [min-max] of 101.5 [0-263] months from the time of mutation diagnosis to the last follow-up, thereby encompassing observation until reaching a median [min-max] age of 56.5 [18-82] years, assuming a lifelong condition. Conclusions: Despite perceptions of clinical insignificance, ongoing uncertainties regarding potential clinical manifestations of MEN2 continue to surround the Y791F variant. There is an ambiguity between sporadic cases and MEN2 associated manifestations leaving the role of regular monitoring open for consideration.