Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline pathogenic variants of DNA mismatch repair (MMR) genes. To diagnose LS, the microsatellite instability (MSI) test or immunohistochemistry of MMR enzymes is used as a conventional clinical screening method for all patients with colorectal and endometrial cancers. Recently, patients with advanced-stage cancers have undergone comprehensive genomic profiling (CGP), which is useful not only for the detection of molecularly targeted personalized therapies, but also for the screening of hereditary cancer syndromes by determining presumed germline pathogenic variants (PGPVs). Between January 2020 and April 2024, 1583 patients underwent CGP at our institute. PGPVs in MMR genes were detected in 19 patients. Although one patient died prior to the disclosure of the results and eight patients declined confirmatory genetic testing, the remaining ten patients underwent confirmatory genetic tests, of whom six were found to have a hereditary origin. Two additional patients were diagnosed with LS using tumor-normal paired CGP. Eventually, a total of eight patients were diagnosed with LS. Herein, we describe two patients with microsatellite-stable cancer who could not be diagnosed using conventional clinical screening or MSI testing. Furthermore, we showed that pathogenic variants of MMR genes do not always correlate with high MSI prediction scores in several cancer types in The Cancer Genome Atlas (TCGA) dataset analysis. These findings highlight the usefulness of CGP as a screening tool to identify individuals with possible LS, especially when conventional criteria and MSI/MMR testing fail.