Multimodal analysis of rare BARD1 missense variant suggests its pathogenicity is conditional

Abstract Hereditary breast cancer involves multiple risk genes, including BARD1, which confers low to moderate risk and is associated with triple-negative breast cancer (TNBC). We report a proband with a primary ER+/PR+/HER2- breast cancer which recurred unilaterally as a TNBC and who later developed endometrial cancer. Clinical germline testing revealed a rare BARD1 missense variant of uncertain significance [c.2258G > T; p.(Gly753Val)]. Whole-exome sequencing of tumors and blood revealed BARD1 loss of heterozygosity and mutational signature 3 – indicative of homologous recombination (HR) repair deficiency – exclusively in the TNBC recurrence. Functional assays demonstrated impaired HR repair via increased PARP inhibitor sensitivity and reduced RAD51 foci formation. We hypothesize that the selective pressure exerted by tamoxifen resulted in breast cancer subtype switching and uncovered the pathogenic potential of the BARD1 p.(Gly753Val) variant. This case illustrates a previously unreported scenario where the pathogenicity of a germline BARD1 variant appears conditional on prior treatment.