For a study, researchers sought to examine the results of comprehensive multigene panel tests based on clinical findings. A prospectively compiled database served as the foundation for this cross-sectional study. The research was carried out at a tertiary hospital. Between March 2014 and December 2019, 381 patients at high risk of hereditary colorectal cancer syndromes were enrolled. The primary goal was to characterize the mutational spectrum using genotype-phenotype concordance and discordance. Germline mutations were found in 89 patients for polyposis hereditary colorectal cancer genes (76 for APC, 4 for PTEN, 4 for STK11, 3 for BMPR1A, 1 for POLE, and 2 for POLD1), 89 patients for nonpolyposis hereditary colorectal cancer genes (41 for MLH1, 40 for MSH2, 6 for MSH6, and 2 for PMS2), and 12 patients for other cancer predisposition (1 in ATM; 2 in BRCA1; 1 in BRCA2; 1 in BRIP1; 1 in MLH3; 1 in NBN; 1 in PMS1; 1 in PTCH1; 1 in TP53; and 2 in monoallelic MUTYH). Direct sequencing tests of 1 or 2 major genes based on phenotype would have missed 48 (25.3%) of 190 mutations due to technical differences (12.1%), less frequent genotype (4.2%), and unclear phenotype (3.7%), and genotype-phenotype discordance (4.7%). The discordance between genotype and phenotype was most likely due to compound heterozygote, a less distinct phenotype, and insufficient information about colorectal cancer risk. This study included a small number of patients who received insufficient follow-up. A comprehensive multigene panel was expected to detect more genetic mutations than phenotype-based direct sequencing, with particular utility in cases of unclear phenotype or genotype-phenotype discordance.