In the NGS era, testing tumor tissues by a comprehensive NGS panel to include BRAF, KRAS, NRAS, MMR genes (MLH1, MSH2, MSH6, PMS2, EPCAM) and a panel of genes associated with other hereditary CRC not only identifies somatic mutations for targeted therapy and prognostication prediction, but also detect double somatic mutations of the MMR genes and potential germline mutations for further confirmation by testing non-neoplastic tissues (34, 35). The gene discussed is MSH2; the disease is colorectal carcinoma.