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Background and Aims: To determine prevalence and clinical utility of pathogenic germline variants (PGV) in gastric and esophageal cancer patients using universal genetic testing approach.Methods: We undertook a prospective study of germline sequencing using an > 80 gene next-generation sequencing platform among patients with gastric and esophageal cancers receiving care at Mayo Clinic Cancer Center between April 1, 2018, and March 31, 2020. Patients were not selected based on cancer stage, family history of cancer, ethnicity, or age. Family cascade testing was offered at no cost.Results: A total of 96 patients were evaluated. Median age was 66 years, 80.2% were male, 89.6% were white. Nearly 39% of the cohort had esophageal cancer, 35.4% gastric cancer and 26% gastroesophageal junction cancers. Approximately half (52%) of the patients had metastatic disease. Pathogenic germline variants (PGV) were detected in 15.6% (n = 15) patients. The prevalence of PGV was 10.8% in esophageal cancer, 17.6% in gastric cancer and 20% in gastroesophageal cancer. Eighty percent of patients with a positive result would not have been detected by screening with standard guidelines for genetic testing. Most PGV detected included genes with high and moderate penetrance related to DNA damage response including BRCA1, BRCA2, PALB2 and ATM.Conclusions: Universal multi-gene panel testing in gastric and esophageal cancers was associated with detection of heritable mutations in 15% of patients. The majority of PGV would not be detected with current screening guidelines and are related to DNA damage response. [ABSTRACT FROM AUTHOR]