Mutations are fundamental to thyroid tumorigenesis and the biological consequences of each specific mutation varies across a spectrum from strong, highly predictive of cancer (BRAF_V600E, TERT_-124C>T), to low drivers being present in both benign and malignant states (RAS, PAX8/PPARg). In addition to strong mutational drivers, multiple microRNA pathways also regulate the development of thyroid tumorigenesis (1, 2). Molecular diagnostics can provide key insights into the nature of thyroid nodules that can guide patient care and management (3). Currently, the two approaches used for diagnosing thyroid nodule progression to cancer are rule-in tests and rule-out tests. These tests are either based upon the detection of oncogenic variants or altered mRNA and micro RNA expression profiles (4, 5). Previously, we reported a combined test which incorporates the advantages of “rule-in and rule-out” tests. In the combined test, specimens are initially tested using Next Gen Sequencing (NGS) based ThyGenX test to detect single nucleotide variants (SNVs) in 5 genes and 6 fusions transcripts (1-5). Here we report the clinical validation of an expanded panel of mutations and RNA fusions, known as the ThyGeNEXT test designed to work in concert with a complementary microRNA (ThyraMIR test) profiling assay. These tests when performed together enable a greater understanding of the role of low driver mutational states without diminishing rule in and rule out diagnostic and predictive testing properties. In addition, we also present a novel risk classification and patient care management algorithm using insights derived from testing >10000 clinical thyroid nodule aspirates.