Abstract Background: Although the role of BRCA1 and BRCA2 has been well studied in women of European ancestry, the contribution of these and other genes associated with hereditary cancers remains unknown in other populations. Here, we utilized panel testing to analyze 94 cancer predisposition genes in African American women (AAW) diagnosed with invasive breast cancer. Methods: 145 self-described AAW who enrolled in the Clinical Breast Care Project from 2001-2012 and had genomic DNA available were identified. Targeted sequencing was performed using the TruSight Cancer panel (Illumina). Pathogenic mutations were identified using VariantStudio and classified as pathogenic, uncertain significance (VUS), or benign using ClinVar. Results: Mean age at diagnosis was 52.1 years (range 25-81 years), and 32% of AAW had a family history. The majority of tumors were ER+HER2- (53%) followed by triple-negative breast cancer (TNBC, 34%). Seven percent of AAW had pathogenic mutations in high-risk genes including BRCA1 (n=7), BRCA2 (n=3), and TP53 (n=1); VUS were detected in BRCA1 (n=1) and BRCA2 (n=2); and an additional woman had a private variant (D2965E) in BRCA2. A further 1% of AAW harbored mutations in the moderate-penetrance gene CHEK2. VUS were also detected in ATM (n=9), CDH1 (n=1), CHEK2 (n=2), MSH2 (n=1), MSH6 (n=5), NBN (n=1), PALB2 (n=4), PMS2 (n=3), RAD51C (n=1), SMAD4 (n=1), TP53 (n=1), and TSC2 (n=1). Conclusions: Although 94 cancer predisposition genes were evaluated, pathogenic mutations in AAW were detected only in four well-established breast cancer predisposition genes (BRCA1, BRCA2, CHEK2, and TP53). Overall mutation frequency was 9%; however, an additional 25% of AAW harbored private variants and VUS, underscoring the critical need to establish the pathogenicity of these variants. The opinions or assertions contained herein are the private ones of the author/speaker and are not to be construed as official or reflecting the views of the Department of Defense, the Uniformed Services University of the Health Sciences, or any other agency of the U.S. Government. Citation Format: Heather L. Blackburn, Craig D. Shriver, Rachel E. Ellsworth. Panel testing to evaluate genetic predisposition to breast cancer in African American women [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B77.