RET Gene Alterations in Clinical Practice: A Comprehensive Review and Database Update

Background/Objectives: The RET (Rearranged during Transfection) gene encodes a receptor tyrosine kinase. RET plays a critical role in embryonic development and postnatal physiology. This review provides a comprehensive overview of RET-associated disorders, focusing on the molecular mechanisms of RET activation, associated clinical phenotypes and therapeutic implications. In addition, we present an updated RET mutation database. Methods: RET mutation database is built through the integration and curation of data from two major RET mutation repositories: the Leiden Open Variation Database (LOVD) and the Cancer Knowledge Base (CKB) as well as information derived from the ClinVar database. Results: To date, 78 pathogenic RET mutations have been identified, among these, 71 (91.0%) are single nucleotide substitutions (missense variants), 2 (2.6%) are deletions, 1 (1.3%) are indels, 2 (2.6%) are nonsense mutations and 1 (1.3%) mutation affecting the introns. A pronounced clustering was observed in exons 10–11, accounting for ~60% of cases, suggesting a potential mutational hotspot with structural or functional relevance. Conclusions: Aberrant RET activation, resulting from activating missense variants, gene fusions, or overexpression, underlies a wide spectrum of human diseases. These include multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma (MTC), Hirschsprung disease, and pheochromocytoma. The existence and use of a database classifying variants in the RET gene plays a fundamental role in molecular diagnostics and personalized medicine.