Abstract[Background] Comprehensive genomic profiling (CGP) expands treatment options for solid tumor patients and identifies hereditary cancers. However, confirmatory tests have been done in only 31.4% of patients who were found to have presumed germline pathogenic variants (GPVs) with a tumor-only test in Japan. Consequently, many GPVs are likely undiagnosed. Analysis of paired tumor and normal specimens enables distinction of somatic and GPVs. GenMineTOP, reimbursed by Japan’s universal national health insurance in August 2023, analyzes tumor/normal paired samples and reports GPVs in 40 genes (updated to 59 genes, based on the ACMG SF v3.2). This study clarifies the landscape of GPVs by using real-world data from GenMineTOP.[Methods] We analyzed 1, 356 patients with solid tumors who underwent GenMineTOP testing in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database between August 2023 and July 2024. C-CAT aggregates nationwide CGP data and allows combined analysis with clinical information. The study focused on GPV detection rates, distribution of targeted genes, and features of genes included in secondary findings. Additionally, GPVs were categorized as "On-Tumor" (associated with the tumor type) or "Off-Tumor" (not associated with the tumor type) according to NCCN Guidelines® and other various guidelines, and the proportion of GPVs detected as Off-Tumor was calculated.[Results] The median age of patients was 61 years (range: 0-90), with equal gender distribution. The most common cancer types were colorectal (15%), soft tissue sarcoma (12%), and brain tumors (11%). Seventy-nine GPVs were detected in 76 patients (5.6%). Patients with detected GPVs had a median age of 56 years (range: 1-87) with an equal gender distribution. However, the age distribution showed that the most common age group was the 70s for males (24.3%, 9/37) and the 40s for females (30.8%, 12/39). The most frequently detected gene was BRCA2 (n = 19), followed by BRCA1 (n = 9), RAD51D (n = 8), and NF1 (n = 8). Cancer types with GPV detection rates exceeding 10% included peripheral nervous system tumors (20%), prostate cancer (12.5%), and ovarian cancer (11.9%).Of the GPVs detected, 44.3% (36/79) were Off-Tumor, including 47.4% (9/19) of BRCA2 patients. In addition, patients with homologous recombination deficiency (HRD)-related genes (ATM, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D) detected included 19 males (median age: 69 years) and 24 females (median age: 54 years). Among males, 57.9% (11/19) were aged 65 years or older.[Discussion] GPVs were identified in 5.6% of patients using GenMineTOP. The high prevalence of Off-Tumor GPVs and elderly male patients highlights the under-recognition of hereditary cancer in this demographic. These findings support the use of paired CGP to improve the diagnosis of hereditary cancers that might otherwise remain undetected.Citation Format:Eri Habano, Miho Ogawa, Kousuke Watanabe, Nana Akiyama, Hyangri Chang, Aya Shinozaki-Ushiku, Masakazu Akahori, Toshimitsu Ichijo, Shuichi Tsutsumi, Kenji Tatsuno, Hiroyuki Aburatani, Hidenori Kage, Katsutoshi Oda. Real-world data on germline pathogenic variants using GenMineTOP, a tumor/normal paired comprehensive genomic profiling test, in Japan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2279.