Mutations in BRCA1 and BRCA2 genes are associated with approximately 45% of families with multiple cases of breast cancer and up to 90% of families with both breast and ovarian cancer. However, a proportion of women with hereditary breast cancer have no identified pathogenic variants in genes predisposing them to breast cancer. To better understand the aetiology of familial breast cancer we are conducting a whole genome analysis of tumours from familial cases with BRCA1 (n=26) or BRCA2 (n=22) germline mutations and cases from families not attributed to BRCA1 or BRCA2 gremlin mutation (i.e. non-BRCA1/2; n=32, including 1 PALB2 carrier and six carriers of unclassified variants in BRCA1 or BRCA2). Biospecimens and clinico-pathological data were obtained from kConFab, the Brisbane Breast Bank and the Australian Breast Cancer Tissue Bank. Whole genome sequencing (WGS) was performed for 80 matched tumour/normal pairs (60x and 30x coverage, respectively). Whole genome methylation arrays were analysed for 67 tumours and RNASeq for 37 tumours. Comparative analysis with data from 99 sporadic breast tumours from The Cancer Genome Atlas is underway to identify potential similarities or differences between familial and sporadic tumours. The complete spectrum of somatic and germline of mutations has been evaluated, including SNPs, indels, copy number changes and structural rearrangements, and mutational signatures. BRCA1, BRCA2 and non-BRCA1/2 tumours exhibited a different burden of mutations, different spectrum of mutational signatures and different telomere lengths. BRCA1 and BRCA2 tumours exhibit highly complex and highly rearranged genomes. In 5 non-BRCA1/2 cases mutational signatures suggests that deficiency in the Homologous Recombination (HR) pathway might be driving the development of those tumours but not through BRCA1 or BRCA2 mutation. We will present our most recent findings in detecting the mechanisms underlying familial breast cancers that in the future could help the management of families where the underlying cause is unclear.