Spectrum of germline pathogenic variants in early-onset breast cancer: a multicentre retrospective study in Malaysia

Abstract

Early-onset breast cancer (EOBC) is an important clinical indication for hereditary cancer assessment, as younger patients with breast cancer (BC) have a higher likelihood of carrying germline cancer predisposition variants compared with unselected BC populations. However, local data on the gene spectrum and diagnostic yield of germline pathogenic/likely pathogenic (P/LP) variants among Malaysian EOBC patients remains limited. In particular, the contribution of non-BRCA cancer predisposition genes, clinicopathological predictors of germline P/LP variants, and the outcomes of different genetic testing approaches is not well characterised. This study aimed to characterise the spectrum of germline P/LP variants, examine their association with clinicopathological characteristics, and compare the diagnostic yield of BRCA-only and multigene panel testing among Malaysian EOBC patients. This multicentre retrospective study included EOBC patients diagnosed at <45 years of age who underwent germline genetic testing between 2020 and 2025. Data were collected from CRM, HKL and Hospital TABTAR. Demographic, clinicopathological, family history and genetic testing data were extracted from medical records. A total of 725 patients were included. Overall, 145 patients (20.0%) carried germline P/LP variants across 14 cancer predisposition genes. BRCA1 was the most frequently identified gene (40.5%), followed by BRCA2 (36.5%), while non-BRCA P/LP variants accounted for 23.0% of positive genetic findings, with PALB2 (5.4%), ATM (4.1%) and TP53 (3.4%) being the most common. In addition, triple-negative breast cancer (TNBC), bilateral BC and positive family history were identified as independent predictors of carrying germline P/LP variants. Diagnostic yield was 23.9% for BRCA-only testing and 19.1% for multigene panel testing. Detection of variant of uncertain significance (VUS) increased with larger panel size, highlighting the importance of careful variant interpretation and genetic counselling. These findings support EOBC as an indication for germline genetic testing and more appropriate referral for genetic counselling and testing.