Background: Genomic profiling through paired tumor/non-tumor analysis can identify pathogenic germline variants (PGV) responsible for inherited cancer syndromes. This can benefit patients and their relatives through cascade testing (CT), preventing many cancer-related deaths. We explored the impact of this strategy for tumor profiling on cancer syndrome diagnosis. Methods: The Tumor Profiling Lab (TPL) sequences cancer specimens and matched normal tissue using the Oncomine Comprehensive Assay (ThermoFisher). A protocol was implemented between the TPL and the Cancer Genetics and Prevention Program (CGPP) by which a notification was sent to oncologists and the CGPP when a PGV was identified. The notification highlights the finding and facilitates referral to CGPP. Our analysis includes data from 1/2018 to 7/2021. Primary outcome: identification of PGV. Secondary outcomes: patients referred and seen by CGPP, and advised for CT. Results: A total of 123 (6.35%) patients with over 20 cancer types had a PGV; for 85 (69.1%) this was a new finding. 36 of the 85 (42.4%) were referred to CGPP and of those, 24 (66.7%) were seen and advised for CT. 4 patients with newly diagnosed PGV had already been seen by CGPP, but either had not undergone genetic testing or had not been tested for the gene in which a PGV was later found. Of the 123 patients with PGV, 74 were not seen by CGPP. 33 (44%) were advised by their oncologist regarding CT for relatives. In total, among patients with newly diagnosed PGV, 51 (60%) were advised for CT. Conclusion: 2/3 of cancer patients in whom paired tumor/normal sequencing analysis identified a PGV had not been previously diagnosed with an inherited cancer syndrome by standard of care approaches. Identification of a PGV resulted in CT advice for 60% of these patients, with hundreds of family members potentially benefitting from preventive measures. Creating more streamlined systems for notifying relatives can result even in greater benefit by reaching more individuals. Baseline demographics Table 1 N = 123 Age at tumor testing, mean (range) 60.4 (10-90) Gender, n (%) Female 62 (50.4) Male 61 (49.6) Stage at tumor testing, n (%) Stage IV 103 (83.7) Stage I-III 20 (16.3) Known PGV, n (%) Known 38 (30.9) New 85 (69.1) Referral to CGPP, n (%) Referred 37 (30.1) Not Referred 61 (49.6) N/A (known to a cancer genetics program*) 25 (20.3) *22 known to CGPP; 3 known to outside programs Seen by CGPP, n (%) Seen 49 (39.8) Not Seen 74 (60.2) Days from referral to visit, median (range) 17 (1-217) Advised for CT (including seen by CGPP)**, n (%) Advised 81 (65.9) Not advised 42 (34.1) ** One patient seen before tumor testing; no identifiable mutation at that visit. After testing, new PGV found, but was not counseled on it. Advised for CT (if not seen by CGPP), n (%) N = 75 Advised 33 (44.0) Not advised 42 (56.0) Citation Format: Christina N. Dimopoulos, Karina Brierley, Joanna Gibson, Zenta Walther, Xavier Llor. Paired tumor/normal clinical sequencing enables identification of patients with pathogenic germline variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5897.