Abstract B143: Genomic analysis of Fanconi Anemia mutations reveals ancestry-associated differences in carrier frequency

Abstract Fanconi Anemia (FA) is a rare genetic disorder caused by pathogenic mutations in one or more of the 23 genes in the FANC gene family. The FA pathway is primarily responsible for double-strand break DNA repair, specifically mending interstrand crosslink (ICL) DNA lesions. Dysfunction in this pathway causes genomic instability, leading to a variety of symptoms, including progressive bone marrow failure, aplastic anemia, and a greatly increased risk of cancer, particularly acute myeloid leukemia (AML), and later in life, squamous cell carcinomas of the head and neck. Given its clinical severity, early diagnosis of FA is crucial for effective treatment and management of the disease. Further, knowledge of an individual’s carrier status could impact family planning decisions and help advise cascade genetic counseling and testing for related individuals. Emerging studies suggest that the carrier frequency of FA-associated mutations may vary across different genetic ancestry groups, potentially contributing to differences in FA and FA-associated cancer prevalence. To investigate the differential prevalence of pathogenic FANC variants by ancestry in the general population, we leveraged data from the gnomAD and All of Us databases to assess FA carrier frequencies across genetic ancestry groups. We used CADD and AlphaMissense computational variant effect prediction tools to identify population-prevalent pathogenic carrier frequencies for variants across the 23 FANC genes and analyzed differences in variant distributions by ancestry. Findings highlight the importance of ancestry in FA variant interpretation and lay the groundwork for future studies investigating the clinical implications of these prevalence disparities in FA, ultimately aiming to refine FA diagnostic and screening approaches across racially and ethnically diverse groups. Citation Format: Andrew L. Araneo, Kyriaki Founta, Nyasha Chambwe. Genomic analysis of Fanconi Anemia mutations reveals ancestry-associated differences in carrier frequency [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr B143.