Background: Although EG cancer is included in Lynch syndrome (LS) and hereditary diffuse gastric cancer (HDGC), the prevalence of HRD-associated germline mutations in patients with EG cancer remains to be elucidated. To determine the potential therapeutic implications, we assessed the prevalence of clinically actionable germline mutations detected by matched tumor-normal sequencing. Methods: The matched tumor-normal DNA were evaluated for somatic (up to 468 genes) and germline (76 genes) alterations under MSK IRB approved protocols. Prevalence of likely pathogenic and pathogenic germline alterations were reported in genes and correlated with clinical and somatic findings. Results: Of 400 consecutive pts with metastatic EG adenocarcinoma: 53% had esophagus/GEJ and 47% gastric cancer. 48 (12%) of patients had clinically actionable mutations conferring cancer susceptibility, including 38 moderate- to high- penetrance mutations. 30 of 400 pts (7.5%) pts had deleterious somatic (n = 17) or pathogenic germline (n = 19) mutations in the most commonly observed HRD genes (ATM, BRCA1, BRCA2). The prevalence of clinically actionable germline mutations among gastric versus esophagus/GEJ tumors was 15.5% and 8.9%, respectively (p = 0.043). Interestingly, one individual harbored both a BRCA1 and an ATM mutation. Germline DNA mismatch repair mutations, diagnostic of LS, were present in only two pts, both with gastric cancer, MSH2 mutations, with both tumors exhibiting a mismatch repair deficient signature. Other germline mutations of interest include: 6 CDH1, 1 TP53, 1 BRIP1, 1 STK11 pts as well as 1 biallelic MUTYH carrier diagnostic of MUTYH-associated polyposis. When available, correlative tumor data, including somatic mutations and loss of heterozygosity in the gene(s) corresponding to the germline mutation will be presented. Conclusions: Clinical NGS in paired germline-tumor DNA samples increases detection of individuals with potential clinically significant germline/somatic mutations. Analysis of therapeutic implications of these HRD mutations is ongoing and updated data will be presented.