Background: GMs in DDR genes, in particular BRCA1/2, are associated with increased risk of cancer, including PDAC. Their identification is crucial for the clinical relevance, the best treatment choice, and the family implications in cancer prevention. However, there are few data regarding the epidemiology and the prognostic role of DDR GMs in PDAC patients (pts). The aim of our study is to determine the prevalence of DDR GMs, their correlation with clinicopathological features and their prognostic role. Methods: Unselected PDCA pts, assessed by BRCA1/2 GM analysis or multigenic panel at our Institution, were retrospectively analyzed. We divided the overall population into three groups based on GMs: pts with pathogenic variants (PVs), pts with variants of uncertain significance (VUS) and pts with no alterations. Clinicopathologic characteristics and treatment data were collected. The incidence of DDR GMs variants and their association with overall survival (OS) were evaluated. Univariate and multivariate analyses for OS were performed. Results: From September 2019 to August 2021, 200 PDAC pts were tested for DDR GMs: all pts were evaluated for BRCA 1/2; 140 pts were tested for further DDR GMs by a multigenic panel. Twenty-five pts (12.5%) had PVs, 45 (22.5%) pts had VUS and 130 (65%) pts had no GMs. BRCA 1-2 PVs were found in 10 pts (5%). Out of 91 pts with metastatic disease, the rate of PVs BRCA1/2 was 8.8%. Among 140 pts tested with multigenic panel, further PVs included: 7 (5%) ATM, 5 (3.6%) MUTYH, 1 (0.7%) TP53, 1 (0.7%) BARD1, and 1 (0.7%) MSH6. The most frequent VUS were: CHECK2 (5%), APC (3.6%), ATM (3.6%) and BRCA2 (3.6%). Regarding cancer family history, a statistically significant difference was reported between the 3 group (76% in PV pts, 82% in VUS pts and 60% in pts with no GMs; p 0.01). No difference was found concerning age (p 0.69), stage at diagnosis (p 0.31) and platinum-exposure (p 0.27). Out of 189 evaluable pts, median OS was 23 months. A significant difference in OS was observed in the 3 groups (30 months in PVs pts, 14 months in VUS pts and 24 months in pts with no GMs, p 0.0006). No factor, including the presence or the type of GMs, age, stage and family history, was significantly associated with OS at the multivariate analysis. Conclusions: In our study, we observed a high incidence of DDR GMs PV (12.5%), beyond BRCA 1/2, regardless of age, stage and family history. Despite retrospective nature of our analysis, small population, and single-institution evaluation, our findings confirm the importance of genetic testing for BRCA1/2 and, where available, of a multigenic test in all PDAC pts, due to the therapeutic implications and cancer risk prevention in patients relatives. The prognostic role of DDR GMs and the impact of VUS remain unclear.