BackgroundCHEK2c.1100delC was the first moderate-risk breast cancer (BC) susceptibility allele discovered. Despite several genomic, transcriptomic and functional studies, however, it is still unclear how exactlyCHEK2c.1100delC promotes tumorigenesis. Since the mutational landscape of a tumor reflects the processes that have operated on its development, the aim of this study was to uncover the somatic genomic landscape of CHEK2-associated BC.MethodsWe sequenced primary BC (pBC) and normal genomes of 20CHEK2c.1100delC mutation carriers as well as their pBC transcriptomes. Including pre-existing cohorts, we exhaustively compared CHEK2 pBC genomes to those fromBRCA1/2mutation carriers, those that displayed homologous recombination deficiency (HRD) and ER− and ER+ pBCs, totaling to 574 pBC genomes. Findings were validated in 517 metastatic BC genomes subdivided into the same subgroups. Transcriptome data from 168 ER+ pBCs were used to derive aTP53-mutant gene expression signature and perform cluster analysis with CHEK2 BC transcriptomes. Finally, clinical outcome ofCHEK2c.1100delC carriers was compared with BC patients displaying somaticTP53mutations in two well-described retrospective cohorts totaling to 942 independent pBC cases.ResultsBC genomes fromCHEK2mutation carriers were most similar to ER+ BC genomes and least similar to those ofBRCA1/2mutation carriers in terms of tumor mutational burden as well as mutational signatures. Moreover, CHEK2 BC genomes did not show any evidence of HRD. SomaticTP53mutation frequency and the size distribution of structural variants (SVs), however, were different compared to ER+ BC. Interestingly, BC genomes with bi-allelicCHEK2inactivation lacked somaticTP53mutations and transcriptomic analysis indicated a shared biology withTP53mutant BC. Moreover, CHEK2 BC genomes had an increased frequency of > 1 Mb deletions, inversions and tandem duplications with peaks at specific sizes. The high chromothripsis frequency among CHEK2 BC genomes appeared, however, not associated with this unique SV size distribution profile.ConclusionsCHEK2 BC genomes are most similar to ER+ BC genomes, but display unique features that may further unravel CHEK2-driven tumorigenesis. Increased insight into this mechanism could explain the shorter survival ofCHEK2mutation carriers that is likely driven by intrinsic tumor aggressiveness rather than endocrine resistance.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13058-023-01653-0.