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Background  The role of the  BARD1  gene in breast cancer (BC) and ovarian cancer (OC) predisposition remains elusive, as published case-control investigations have revealed controversial results. We aimed to assess the role of deleterious  BARD1  germline variants in BC/OC predisposition in a sample of 4920  BRCA1/2 -negative female BC/OC index patients of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC).    Methods  A total of 4469 female index patients with BC, 451 index patients with OC, and 2767 geographically matched female control individuals were screened for loss-of-function (LoF) mutations and potentially damaging rare missense variants in  BARD1 . All patients met the inclusion criteria of the GC-HBOC for germline testing and reported at least one relative with BC or OC. Additional control datasets (Exome Aggregation Consortium, ExAC; Fabulous Ladies Over Seventy, FLOSSIES) were included for the calculation of odds ratios (ORs).    Results  We identified LoF variants in 23 of 4469 BC index patients (0.51%) and in 36 of 37,265 control individuals (0.10%), resulting in an OR of 5.35 (95% confidence interval [CI] = 3.17–9.04;  P  < 0.00001).  BARD1- mutated BC index patients showed a significantly younger mean age at first diagnosis (AAD; 42.3 years, range 24–60 years) compared with the overall study sample (48.6 years, range 17–92 years;  P  = 0.00347). In the subgroup of BC index patients with an AAD < 40 years, an OR of 12.04 (95% CI = 5.78–25.08;  P  < 0.00001) was observed. An OR of 7.43 (95% CI = 4.26–12.98;  P  < 0.00001) was observed when stratified for an AAD < 50 years. LoF variants in  BARD1  were not significantly associated with BC in the subgroup of index patients with an AAD ≥ 50 years (OR = 2.29; 95% CI = 0.82–6.45;  P  = 0.11217). Overall, rare and predicted damaging  BARD1  missense variants were significantly more prevalent in BC index patients compared with control individuals (OR = 2.15; 95% CI = 1.26–3.67;  P  = 0.00723). Neither LoF variants nor predicted damaging rare missense variants in  BARD1  were identified in 451 familial index patients with OC.    Conclusions  Due to the significant association of germline LoF variants in  BARD1  with early-onset BC, we suggest that intensified BC surveillance programs should be offered to women carrying pathogenic  BARD1  gene variants.    Electronic supplementary material  The online version of this article (10.1186/s13058-019-1137-9) contains supplementary material, which is available to authorized users.

Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer