Molecular Diagnostics in Thyroid Nodules: Current Applications, Clinical Value, and Future Perspective

ABSTRACT Molecular diagnostics have become an important adjunct to ultrasonography and fine‐needle aspiration (FNA) for thyroid nodules, especially in Bethesda III/IV cytology where malignancy risk is uncertain. This narrative review summarizes the diagnostic and prognostic value of key genomic drivers (BRAF V600E, RAS, RET, TERT, and selected fusions) and the performance of major commercial assays, and discusses how they can be integrated into practical care pathways. BRAF V600E, particularly when co‐occurring with TERT promoter mutations, acts as a strong rule‐in marker for aggressive disease, whereas RAS variants are common in follicular‐patterned, often indolent lesions and have variable positive predictive value, requiring cautious interpretation. Among commercial tests, Afirma Genomic Sequencing Classifier (GSC) functions mainly as a high–negative predictive value rule‐out tool, while ThyroSeq v3 and ThyGeNEXT–ThyraMIR provide both strong rule‐out performance and useful rule‐in information when high‐risk alterations are detected; smear‐based RosettaGX Reveal is promising but less extensively validated. When embedded in a structured pathway, these assays can reduce unnecessary diagnostic surgery and better target intensive treatment, although verification bias, heterogeneous performance, limited long‐term outcome, and cost‐effectiveness data, and the need for further validation of liquid biopsy and AI‐driven approaches remain important gaps.