Abstract 1466: Comprehensive analysis of breast and ovarian cancer-identified RAD51D variants

Abstract The RAD51 paralogs are essential genes in coordinating the early steps of homologous recombination (HR)-mediated repair of DNA double strand breaks (DSBs). Currently, there are over 300 epidemiology studies linking a single mutation or polymorphism in one of the five canonical RAD51 paralogs to cancer predisposition and tumorigenesis. As one of the most frequently mutated RAD51 paralogs, mutations in RAD51D have been identified in 5% of hereditary ovarian cancers and pathogenic variants are associated with a 25% lifetime risk for breast cancer. We have uncovered more than 160 patient-identified missense variants in RAD51D, the majority of which are clinically classified as variants of unknown significance (VUS) and have little to no prior functional analysis. Herein, we have performed a comprehensive screen of all known missense RAD51D VUS identified in breast and ovarian cancer patients, identifying 7 potentially pathogenic variants which disrupt native protein interactions, reduce HR proficiency, and exhibit varying degrees of sensitivity to the typical chemotherapeutics used to treat HR-deficient (HRD) cancers. In defining the functional consequences of RAD51D VUS, we hope to inform formal clinical classification of these VUS in hopes of better estimating cancer risk and leverage precision therapeutic approaches for mutation carriers. Citation Format: Kristie Darrah, Katherine Oppenheimer, Nicole Banks, Phoebe Parker, Ella Roberts, Gayatri Ganesan, Kara Bernstein. Comprehensive analysis of breast and ovarian cancer-identified RAD51D variants. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1466.