OBJECTIVES/GOALS: My research aims to discover African American breast cancer genetic risk factors. Interested in genetic predisposition, I search for inherited variants that could explain why African American women are disparately diagnosed at younger ages and with aggressive subtypes compared to other ethnicities. METHODS/STUDY POPULATION: Our study cohort, the Alabama Hereditary Cancer Cohort (AHCC), consists of African Americans that have had a breast cancer diagnosis indicative of hereditary breast cancer. Whole genome sequencing is conducted for AHCC breast cancer cases. Hypothesizing that African American-specific protein-truncating variants explain inherited risk, our control cohort consists of whole exome sequencing data of (~2500) African Americans from the Type 2 Diabetes Exome Sequencing Project on dbGAP. Single variant and gene-based association tests are being conducted to identify risk variants/genes. Prime editing is conducted to introduce risk variants into cancer cell lines for functional analyses. RESULTS/ANTICIPATED RESULTS: Preliminary studies, involving 60 breast cancer cases, have already revealed multiple African American-specific genetic variants in the nuclear and mitochondrial genome that are statistically linked to breast cancer risk. We are in the process of increasing our breast cancer sample size, aiming for significantly higher confidence. Prime editing for selected novel variants has begun in breast cancer cell lines. Functional assays will then be carried out to observe differences in cell proliferation, cell migration, and spheroid formation in the genetically edited compared to unedited cell lines. DISCUSSION/SIGNIFICANCE: African Americans are underrepresented in breast cancer research. This study reduces research participation gaps and identifies genetic risk variants, leading to better risk assessments and screening methods. Such discoveries can also lead to new therapeutic targets, reducing breast cancer deaths.