The correlation between presence of mutations and malignancy is imprecise. Among 967 Bethesda Type III, IV, and V nodules, the detection of any mutation conferred the risk of histologic malignancy of 88, 87, and 95%, respectively (83). However, even in nodules with no detected mutations, the malignancy rates were 6, 14, and 28%, respectively. A systematic review by our group included 8,162 patients, of whom 42.5% had benign lesions (84). Among the benign lesions, RAS mutations, RET/PTC rearrangements, and PAX8/PPAR-gamma rearrangements were present up to 48, 68, 55% of the time, respectively. Thus, benign nodules frequently harbor mutations, while some malignant lesions harbor no detected mutations. The combination of the variable and potentially high level of mutations among benign nodules may explain the low specificity and PPV seen in Afirma. Furthermore, their prominence in benign lesions may also challenge the reported PPV of Thyroseq V2.