Background: Prevalence of pathogenic or likely pathogenic germline variants (PGVs) in patients with PDAC varies across populations. There is limited information on the prevalence of PGVs among Mexican patients with PDAC. We prospectively tested an unselected cohort of newly diagnosed PDAC patients using a comprehensive gene panel in order to estimate the prevalence of BRCA1/2, and other germline mutations associated with HPC. Methods: The protocol was approved by the ethics committee at each institution: INCMNSZ, INCAN, and CM ABC Observatorio. Key inclusion criteria: age > 18 years and PDAC diagnosed within 6 months of inclusion. Patients were enrolled consecutively, regardless of age, personal or family history of cancer, known hereditary cancer syndrome, or stage of the disease. Written informed consent was obtained before any procedure. Clinical variables including family history of cancer were collected. We used the 84-gene Invitae Multi-Cancer Panel. Genetic testing had no cost for patients. Patient characteristics and family history were summarized using descriptive statistics (IBM SPSS Statistics Version 25). The trial was registered on Clinical Trials (NCT05305001). Results: From August 2020 to June 2022, 119 patients with newly diagnosed PDAC were identified. Of these, 107 patients were included: 58% women, median age was 63 y/o, clinical stages at diagnosis were: I (24%), II (22%), III (6%), and IV (48%). All patients had Hispanic ancestry except one (Ashkenazi Jewish). Only 7.5% (n = 8) had a personal history of other cancer, mainly breast cancer (N = 3); 62% had a family history of any cancer, while 47.6% had a first-degree relative (FDR) with any cancer. 11% (n = 12) had family history of pancreatic cancer (PC), and 9% (n = 10) had an FDR with PC. Five patients met clinical criteria for hereditary cancer syndrome: familial pancreatic cancer (4) and Lynch syndrome (1). PGVs were identified in 17.8% (n = 19) of patients. The prevalence of PGVs in genes associated with autosomal dominant risk of PC was 11.2%: CDKN2A(5.6%), ATM (3.7%), BRCA2 (0.93%), and MSH6 (0.93%). Two patients had a PGV associated with autosomal dominant predisposition to other cancers (CHECK2 and NF1). Six patients (5.6%) had PGVs associated with autosomal recessive predisposition to rare syndromes with increased cancer risk other than PDAC (MUTYH, RECQL4, FH and WRN). Variants of uncertain significance were present in 42% of patients. Conclusions: In Mexican patients with PDAC, the prevalence of PGVs on BRCA1/2 is < 1%. The prevalence of PGVs in other susceptibility genes is 11%. Our results support the role of universal germline testing in Mexican patients with PDAC using a comprehensive gene panel. Selective testing for BRCA1/2 is discouraged.