Abstract Background: The prevalence of pathogenic BRCA mutations in high hereditary risk breast cancer patients (pts) in ethnic Lebanese Arab women was 5.6% in a study published in 2015 (El Saghir, et al. The Oncologist). In this study, we look at real world practice prevalence of BRCA mutations among pts with breast and/or ovarian cancer referred for testing because of positive family history (FH) and/or young age at the American University of Beirut Medical Center (AUBMC). Methods: The study was approved by the Institutional Review Board at AUBMC. We retrospectively collected clinical, radiological, pathological and genetic information on breast and ovarian cancer pts at a high hereditary risk for whom Sanger sequencing of all coding exons and immediately flanking intronic regions of BRCA1 and BRCA2 was performed between January 1, 2010 and Jan 1, 2019 at AUBMC. Between Jan 2019 and Aug 2020, Next Generation Sequencing (NGS) of 70 cancer-associated genes was referred to and done in Centogene labs (Germany). 346 subjects were included in the study; 235 pts with breast and/or ovarian cancer, and 101 subjects of young age or with a positive family history. Results: 210 pts had breast cancer (209 females, 1 male); 81 were diagnosed at age ≤40, 81 aged 41-50, and 48 aged >50. 185 pts had BRCA sequencing and 25 had NGS panel testing. 31 pts had ovarian cancer; 28 had BRCA testing and 3 had NGS. 3 pts had ovarian and breast cancer; all had Sanger sequencing, 1 male pt with both breast and prostate cancers had BRCA testing. The 101 subjects who were tested in the setting of positive FH of cancers or a known deleterious mutation in first degree family members were either target tested for the known familial mutation or had BRCA screening. The incidence of BRCA1 and BRCA2 mutations in women with breast cancer was 8.5% (18/210 patients) and 19.3% (6/31 patients) in women with ovarian cancer. Of the 3 pts who had both breast and ovarian cancer, 1 had a BRCA1 mutation. Almost all patients with hereditary breast cancer had a positive FH and the majority were < 40 years of age. 8 out of 13 BRCA1 pts had Triple Negative disease (61%). Of the 101 subjects with no history of cancer, 9 out of 30 with relatives who had BRCA1 mutation carried the same mutation, and 3 out of 15 with BRCA2 carried the mutation. The remaining 56 pts were tested because of positive FH; 3 out of 56 had a pathogenic mutation (1 BRCA1, 1 BRCA2 and 1 RAD51D). Of the 28 pts who had NGS panel sequencing, 1 patient had RAD51D, 1 had a PALB2 mutation, 1 had BARD1 and 1 had APC risk variant. Conclusions: In this real-world practice study of patients and subjects referred for germline mutation testing. BRCA mutation rate in pts with breast cancer was 8.5% (18/210) and 19% in ovarian cancer (6/31). Young age (< 40 years) and a positive FH are the most useful criteria to select pts with breast cancer for mutation testing, especially in the setting of limited resources. This is the first study to report a 20% rate of BRCA pathogenic variants in patients with ovarian cancer in Lebanon and Arab countries; we highlight the need to refer all ovarian cancer pts for counseling and genetic testing. NGS is important to detect mutations other than BRCA1 and BRCA2 in our population where 50% of cases are below age 50. Table 1. Incidence of BRCA1/2 mutations, age, and family history in pts with breast and ovarian cancer. Citation Format: Nagi El Saghir, Nadine Safi, Ahmad Masri, Firas Kreidieh, Deborah Mukherji, Nada Assaf, Rami Mahfouz, Hiba Moukadem. A Real-World Study of BRCA1 and BRCA2 Germline Mutations among High Hereditary Risk Subjects and Patients with Breast and Ovarian Cancer in Lebanon [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-17.