BRAF gene mutations occur in a variety of human malignancies including approximately 10% of colorectal cancers (CRC), 45% of papillary thyroid carcinomas (PTC), 50% of melanomas, virtually all hairy-cell leukemias (HCL), and 5-10% of gastrointestinal stromal tumors (GIST) that are negative for KIT and PDGFRA mutations. The most common BRAF mutation is the c.1799T>A (V600E) substitution. In CRC, this mutation has been associated with a limited clinical response to epidermal growth factor receptor (EGFR) targeted therapies (cetuximab or panitumumab). As a complement to KRAS mutation analysis, BRAF V600E mutation detection may predict response to these therapies. In addition, BRAF V600E mutations are found in sporadic microsatellite instability high (MSI-H) CRC cases, but not in hereditary non-polyposis colorectal cancers (HNPCC). Therefore, determination of BRAF mutation status may help to differentiate sporadic vs. germline MSI-H colorectal cancers. BRAF V600E mutation testing may also aid in the diagnosis of papillary thyroid carcinoma, since benign thyroid neoplasms are not associated with BRAF mutation. In melanoma, the V600E and V600K mutations may predict response to BRAF targeted therapies. This test qualitatively detects the BRAF c.1799T>A (V600E) and BRAF c.1798_1799GT>AA (V600K) mutations in formalin fixed paraffin-embedded tissues, fresh/frozen tissue, peripheral blood, and bone marrow. BRAF mutations other than V600E and V600K will not be detected. Analytic sensitivity is 5% mutation.