Prevalence and Predictors of Additional Variants Identified by Whole- Genome Sequencing in BRCA1/2 Mutation-Negative Breast Cancer Patients

Abstract Background: The aim of this study was to evaluate the prevalence and clinical significance of non-BRCA germline pathogenic variants (PVs) or likely pathogenic variants (LPVs) identified by whole-genome sequencing (WGS) in Korean BRCA1/2 mutation-negative breast cancer patients. Methods: A total of 871 BRCA1/2 mutation-negative breast cancer patients underwent WGS between May 2020 and December 2022. The frequency of PVs or LPVs was analyzed, and clinicopathologic characteristics, treatment patterns, and oncologic outcomes were compared between variant-detected and non-detected groups. Results: In 43 of 871 patients (4.9%), at least one PV or LPV was identified across 16 genes, with PALB2 and ATM being most frequently detected. Detected variants were significantly associated with advanced tumor stage, younger age, premenopausal status, and higher rates of neoadjuvant chemotherapy. Patients aged ≤ 40 years with ≥ 2 affected family members showed a detection rate of 20.0% (OR = 5.10, p = 0.034). Distinct genotype-phenotype correlations were identified, with PALB2, BARD1, and MSH2 variants linked to triple-negative breast cancer and TP53 mutations to HER2-positive disease. Conclusions: WGS identified clinically significant non-BRCA germline variants in 4.9% of BRCA1/2-negative breast cancer patients, with distinct genotype-phenotype correlations and significant associations with adverse clinicopathologic features. These findings support the integration of WGS into hereditary breast cancer risk assessment, particularly in patients with early-onset disease or strong family history, where conventional panel testing may fail to capture the full spectrum of germline risk.