Abstract Background: Our knowledge of the prevalence of germline mutations associated with pancreatic cancer risk largely came from studies conducted in the Caucasian population. Therefore, there is an urgent need to characterize germline mutations of pancreatic cancer susceptibility genes in the non-Caucasian populations. In this study, we comprehensively analyzed germline mutations in known and candidate pancreatic cancer susceptibility genes in a large Chinese pancreatic duct adenocarcinoma (PDAC) cohort. Methods: Unselected PDAC patients were recruited from 2017 to 2020 and their genomic DNA sample was profiled by a 139-gene NGS panel. We quantified the prevalence of deleterious germline mutations in this Chinese cohort and compared it with published PDAC germline mutation profiling data. Results: In this 546 Chinese PDAC patient cohort, 64 deleterious germline mutations were found in 63 (11.5%) patients. Thirty-one (5.7%) patients carried a deleterious mutation in a pancreatic cancer susceptibility gene: 15 (2.7%) with BRCA1 (n =3) or BRCA2 (n =12) mutations, five with ATM, seven with PALB2, two with MSH6 and one each with a mutation in CDKN2A or TP53. Moreover, 24 (4.4%) patients had deleterious mutations in additional DNA damage repair (DDR) genes including BLM (n =1), NBN (n =1), RAD50 (n =1), RAD51D (n =2), RECQL4 (n =1), WRN (n =2) of the homologous recombination repair (HRR) pathway, ERCC2 (n =1), ERCC4 (n =1), ERCC5 (n =1) of the nucleotide excision repair (NER) pathway, BRIP1 (n =2), FANCC (n =1), FANCD2 (n =2), FANCM (n =2) of the Fanconi anemia (FA) pathway, MSH3 (n =2), PMS2 (n =1) of the mismatch repair (MMR) pathway, MUTYH (n =3) and MRE11A (n =1). The average age at diagnosis of patients with PDAC identified as having a germline mutation in a known (ATM, BRCA1, BRCA2, CDKN2A, MSH6, PALB2 and TP53) pancreatic cancer susceptibility gene was 54.2 ± 10.0 years, significantly lower than the average age of the patients without an identifiable susceptibility gene mutation (60.3 ± 10.6 years; P =0.002). We also compared PDAC-associated germline mutation frequency between our cohort (n =546) and the Mayo Clinic cohort (n =3030) to determine the similarity and difference of PDAC germline mutation landscape between Chinese and Caucasian populations. Of note, the mutation frequencies of ATM and PALB2 were 0.91% and 1.28% in our cohort, significantly lower and higher than 2.28% of ATM (P<0.05) and 0.40% of PALB2 (P =0.02) in the Mayo Clinic cohort, respectively. Conclusions: We found that nearly 12% patients in this Chinese PDAC cohort carry deleterious germline mutations, mainly in established pancreatic cancer susceptibility genes and DDR genes. Our data indicated that the PDAC germline mutation landscape of Chinese population is largely similar to that of the Caucasian population and the NCCN PDAC genetic screen guideline can be applied to the clinical management of PDAC patients of Asian descent. Citation Format: Zhiming Zhao, Xiaomo Li, Fei Wang, Tonghui Ma, Rong Liu. Germline mutation landscape in a large cohort of Chinese pancreatic cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2557.