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Background  The ataxia telangiectasia mutated ( ATM ) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in  ATM  deleterious variant carriers have been described, but identification of an  ATM -associated tumour signature may help in patient management.    Methods  To characterise hallmarks of  ATM -associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of  ATM -associated tumours was compared with that of 599 patients with no  BRCA1  and  BRCA2  mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from  ATM  loss-of-function variant carriers with available frozen material.    Results  We found that  ATM -associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the  ATM  locus at 11q22–23. Unlike tumours in which  BRCA1  or  BRCA2  is inactivated, tumours arising in  ATM  deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for  ATM  testing and harbour driver mutations in potentially ‘druggable’ genes that would allow patients to be directed towards tailored therapeutic strategies.    Conclusions  Although  ATM  is involved in the DNA damage response,  ATM -associated tumours are distinct from  BRCA1 -associated tumours in terms of morphological characteristics and genomic alterations, and they are also distinguishable from sporadic breast tumours, thus opening up the possibility to identify  ATM  variant carriers outside the ataxia-telangiectasia disorder and direct them towards effective cancer risk management and therapeutic strategies.    Electronic supplementary material  The online version of this article (10.1186/s13058-018-0951-9) contains supplementary material, which is available to authorized users.

Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers