Abstract PS3-03-11: Hereditary Breast Cancer Beyond BRCA1/2: Real-World Value of Cascade Testing in Southern Europe cohort

Abstract Background: Multi-gene panel testing has expanded the identification of hereditary breast cancer syndromes. ESMO Precision Oncology Working Group recently published recommendations advising against routine testing of certain genes suggesting minimal mortality benefit (ATM, CHEK2). We present the germline findings from a large, single institution cohort in Southern Europe, focusing on the diagnostic yield of high- and moderate-penetrance genes and the clinical context of variant identification. Methods:We conducted a retrospective analysis of patients (pts) referred to our Hereditary Cancer Genetic Counseling Unit between May 2023 and April 2025. Variant classification followed American College of Medical Genetics (ACMG) criteria. Results: From a total of 518 pts referred for counseling, 387 were tested and included in the analysis (median age 57). Overall, 91 pts (23.5%) carried a pathogenic/likely pathogenic (P/LP) variant (Class 4/5) and 34 (8.8%) had a variant of uncertain significance (VUS). Among the 151 (39%) patients with a personal history of BC, the specific diagnostic yield for a P/LP variant was 14.56% (n = 22), while the VUS rate was 15.2% (n = 23). Among P/LP carriers, 51 (56%) were in high-penetrance breast cancer genes: BRCA1 (n = 24), BRCA2 (n = 24) and PALB2, PTEN, CDH1 (n = 1 each). 36 of 51 (70.5%) of these carriers were identified via cascade testing of healthy relatives. 18 of 91 pts (19.7%) P/LP variants were found in moderate-penetrance genes: ATM (n =9), CHEK2 (n = 6), RAD51C (n = 2), BRIP1 (n = 1). Of note, 11 variants (61%) were identified through cascade testing rather than personal history of cancer. Conclusion: In this real-world cohort, nearly a quarter of individuals undergoing testing carried a clinically significant germline variant. While BRCA1/2 remain dominant, a substantial number of variants in genes like ATM, CHEK2, and RAD51C were discovered through cascade testing, mainly in unaffected carriers. This highlights the clinical challenges surrounding the moderate penetrance genes, including appropriate follow-up and counseling strategies. Citation Format: J. CLAROS, I. SISO, M. ECHARRI, D. MORCHON, L. PIZARROSO, J. MESA, C. ORTEGA, A. GARRIDO, C. PERNAUT, H. FRAILE, A. PEÑALVER, B. ALONSO, A. LOPEZ. Hereditary Breast Cancer Beyond BRCA1/2: Real-World Value of Cascade Testing in Southern Europe cohort abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-03-11.