Analysis results identified 6 high-risk genes associated with ACC, of which the mutation rates in ACC tissues were significantly higher than those in ACA or normal adrenal gland tissues, including ZNRF3, TP53, ARMC5, APC, RB1, and PRKAR1A. We proposed the concept of SHGM defined as the sum of mutated high-risk genes detected in ACC tissues, and the rates of SHGM > 0 and SHGM > 1 in ACC were significantly higher than those in ACA tissues, which suggest SHGM might be potential to assist the differential diagnosis of ACC with ACA, especially for ACC with small tumor size. Here, RB1 is linked to adrenal cortex carcinoma.