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

<b>Background/Objectives:</b> The <i>RET</i> (Rearranged during Transfection) gene encodes a receptor tyrosine kinase. <i>RET</i> plays a critical role in embryonic development and postnatal physiology. This review provides a comprehensive overview of <i>RET</i>-associated disorders, focusing on the molecular mechanisms of <i>RET</i> activation, associated clinical phenotypes and therapeutic implications. In addition, we present an updated <i>RET</i> mutation database. <b>Methods:</b><i>RET</i> mutation database is built through the integration and curation of data from two major <i>RET</i> mutation repositories: the Leiden Open Variation Database (LOVD) and the Cancer Knowledge Base (CKB) as well as information derived from the ClinVar database. <b>Results:</b> To date, 78 pathogenic <i>RET</i> 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. <b>Conclusions</b>: Aberrant <i>RET</i> 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 <i>RET</i> gene plays a fundamental role in molecular diagnostics and personalized medicine.