C611Y Germline Variant in Multiple Endocrine Neoplasia Type 2A in Denmark 1930-2021: A Nationwide Study.

: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare hereditary cancer syndrome caused by pathogenic variants in the rearranged during transfection () gene and is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), primary hyperparathyroidism (PHPT), cutaneous lichen amyloidosis (CLA), and Hirschsprung's disease. Phenotypic data on the C611Y variant remain sparse. Consequently, we aimed to establish a clinical risk profile. : We conducted a nationwide study of all cases (n = 128) born after 1 January 1930 and recognized as carrying the C611Y variant in Denmark before 1 April 2021. : The median follow-up after birth was 47 years (range, 3-92). Age-related penetrance at age 70 years for MTC was 98% (CI, 91-100), for PHEO 24% (CI, 16-37), and for PHPT 10% (CI, 5-20). None had CLA or Hirschsprung's disease. The age-related progression of MTC was significant ( < 0.001). The mean age at T0N0M0 was 16 years (CI, 12–20), at T1-4N0M0 38 years (CI, 34–42), at TxN1M0 45 years (CI, 38–53) and at TxNxM1 49 years (CI, 36–61). At the last follow-up, 56% of thyroidectomized cases (n = 103) were biochemically cured. Overall survival at 70 years was 74% (CI, 59-84). : C611Y is associated with a very high penetrance of MTC and a low penetrance of PHEO and PHPT. CLA and Hirschsprung's disease almost never occur. MTC seems moderately aggressive, but large variability can be seen. Overall survival may be comparable to that of the general population.