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Recognizing African American health and research disparities, there is a need to better understand African American breast cancer risk. Our group has established the Alabama Hereditary Cancer Cohort to aid in identifying risk variants associated with African American hereditary breast cancer. We have identified several suspected risk variants using next-generation sequencing technologies, including a low-frequency African American-specific splicing variant in FANCD2/FANCI-associated nuclease 1 (FAN1). FAN1 is an exo/endonuclease involved in DNA inter-strand crosslinking repair. There has been speculation that FAN1 could be a breast cancer susceptibility gene because FAN1 is in the Fanconi Anemia pathway with known breast cancer susceptibility genes, BRCA1 and BRCA2. This splicing variant, FAN1 c.3057+1G>A, does not interfere with the coded protein, but alters the donor splice site of exon 14, adding 34 bases to the beginning of the 3’ untranslated region. Interestingly, it has an allele frequency of 3.6% in the general African American population but was found in 5.1% of African American breast cancer cases in the Alabama Hereditary Cancer Cohort. Extremely rare in European Americans overall; it was not detected in any European American breast cancer cases. Functionalizing FAN1 c.3057+1G>A and other identified mutations is important to demonstrate pathogenicity. Our group uses prime editing to introduce variants of interest into selected cell lines. Prime editing is an innovative gene-editing technique that can introduce base substitutions, insertions, and deletions into the genome without the need for double-stranded DNA breaks or donor DNA. Upon gene-editing, cell proliferation, invasion, migration, and other cellular characteristics that contribute to tumorigenesis are investigated. Overall, it is imperative to identify African-American breast cancer risk variants and understand how they play a role in disease pathogenesis, leading to better risk assessment and novel therapeutics. Citation Format: Sheniqua R. Glover, Cierla McGuire Sams, Madison Bishop, Troy LoBue, Issac Mcneely, Nancy D. Merner. FAN1 splice variant as a possible risk variant for African American hereditary breast cancer and understanding its role in tumorigenesis [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C041.