S409Y Germline Mutation and Associated Medullary Thyroid Carcinoma.

Inherited medullary thyroid carcinoma (MTC) is primarily caused by mutations that are commonly localized in exons 5, 8, 10, 11, and 13-16. In this study, we report pedigrees for individuals with MTC that harbor a germline S409Y variant within exon 6 of the proto-oncogene. Targeted sequencing was used to diagnose four apparently sporadic MTC index cases carrying the germline S409Y (c.1226 C>A) variant. Subsequently, 27 relatives of these individuals underwent clinical and genetic assessments and/or thyroid surgery. Furthermore, analyses and assays were performed to predict or verify the potential oncogenic activity of the S409Y variant. Overall, 15 of 31 participants were found to carry the S409Y variant. Of these, 6 presented with isolated MTC (mean age 50.2 years; range 41-75 years), of which 3 presented with neck lymph node metastases and 2 presented with distant liver or lung metastases. Among the remaining 9 carriers, 3 (mean age 56 years; range 41-76 years) had elevated serum calcium-stimulated calcitonin (sCtn) or concurrent marginally elevated serum calcitonin (Ctn) levels, whereas the other 6 (mean age 37.5 years; range 14-52 years) exhibited typical Ctn/sCtn levels ( < 0.05). None of the 15 carriers in these 4 families presented clinical evidence of pheochromocytoma, hyperparathyroidism, or Hirschsprung's disease. analyses revealed that S409Y was a "possibly damaging" mutation that could affect the RET protein inter-domain interface. An assay revealed that the phosphorylation level of RET tyrosine 905 was relatively higher in the S409Y mutant than in wild-type (WT) RET. Moreover, transfection of HEK 293 cells with S409Y enhanced the phosphorylation activity of AKT, ERK pathways, and it increased cell proliferation compared with WT RET, but to a lesser degree than that for the C618Y and C634Y mutations. This study demonstrates that the novel germline S409Y variant is likely pathogenic and is associated with lower penetrance of MTC than that for the C618Y and C634Y mutations. Individuals with S409Y should be managed using a personalized approach, and additionally, "at-risk" family members should be evaluated. Additional studies are needed to elucidate the correlation between the S409Y mutation and multiple endocrine neoplasia type 2-specific tumors.