Background: BRCA mutations are responsible for a significant proportion of hereditary breast and ovarian cancers. However, other cancer susceptibility genes are also associated with an increased risk of developing breast cancer (BC). In Mexico, approximately 15% of patients with BC have been identified with BRCA mutations. Despite our growing understanding of BRCA mutations, the contribution and characterization of non-BRCA mutations in Mexican patients with a BC diagnosis remains unknown. We aimed to investigate the spectrum of BC-associated mutations among Mexican patients with BC referred for genetic cancer risk assessment (GCRA) in the multinational Clinical Cancer Genomics Community Research Network (CCGCRN). Methods: Mexican patients with a primary BC who were enrolled in the IRB-approved CCGCRN registry protocol and underwent genetic counseling and multigene panel testing (MGPT) were included. Pathogenic and likely pathogenic variants (PV) in genes associated with increased BC risk were used for analyses. Clinical and demographic characteristics of BRCA and non-BRCA carriers were compared. Results: From December 2012 to February 2020, 725 Mexican patients with BC who had MGPT results with a median age (years) of 41 (range 25-76) were included. 142 (19.6%) patients carried a BC-associated PV. Of these, 98 (69.0%) carried BRCA PVs: 58 in BRCA1 (41.5%) and 40 in BRCA2 (26.7%). PVs in other BC-associated genes (n = 42) accounted for 29.5% of all observed PVs and were distributed as follows: PALB2 (n = 13), CHEK2 (n = 11), RAD51C (n = 6), ATM (n = 3), PTEN (n = 3), TP53 (n = 3), BRIP1 (n = 2), and CDH1(n = 1). Other actionable genes represented 3.5% of all PVs (PMS2 [n = 3]; MSH6 [n = 1]; MSH2 [n = 1]). Suspected founder mutations in Latinas, PALB2 c.2167_2168delAT (n = 5) and CHEK2 c.707T>C (n = 9), represented 33.3% (n = 14/42) of the detected non-BRCA PVs. Mean age at first cancer diagnosis (years) for BRCA and non-BRCA carriers was: 37 (range 26-58) and 42 (range 25-76) (pBRCA PVs had a significantly greater proportion of triple-negative (TN) tumors compared to non-BRCA PVs (45.2% vs 9.5%; pConclusion: A significant proportion of Mexican women carried a BC-associated mutation and a third were non-BRCA PVs. Among non-BRCA PVs, recurrent PALB2 and CHEK2, which had previously been characterized in BRCA-negative US Latinas with BC, were the most common and confirms their presence and clinical impact in Mexico. BRCA carriers were younger and more commonly had the TN molecular subtype. Citation Format: Yanin Chavarri-Guerra, Cynthia Villarreal-Garza, Gubidxa Gutierrez Seymour, Dione Aguilar y Mendez, Jazmin Arteaga-Vazquez, Servando Cardona-Huerta, Adrian Daneri-Navarro, Azucena del Toro Valero, Alejandro Mohar-Betancourt, Andrés Rodríguez-Faure, Jose Luis Rodriguez-Olivares, Gregorio Quintero Beulo, Danielle Castillo, Kai Yang, Joseph Herzog, Rosa Mejia, Sharon Sand, Jeffrey N Weitzel. The spectrum of germline susceptibility gene variants in Mexican patients with breast cancer (BC): A Prospective Multicenter study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-15.