Gene panel testing of 5589 <italic>BRCA1/2</italic>‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer.

Abstract: The prevalence of germ line mutations in non‐<italic>BRCA1/2</italic> genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic <italic>BRCA1/2</italic> mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (<italic>ATM</italic>,<italic> CDH1</italic>,<italic> CHEK2</italic>,<italic> NBN</italic>,<italic> PALB2</italic>,<italic> RAD51C</italic>,<italic> RAD51D,</italic> and <italic>TP53</italic>). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the <italic>CHEK2</italic> gene (2.5%), followed by <italic>ATM</italic> (1.5%) and <italic>PALB2</italic> (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for <italic>ATM</italic> (OR: 3.63, 95%CI: 2.67–4.94), <italic>CDH1</italic> (OR: 17.04, 95%CI: 3.54–82), <italic>CHEK2</italic> (OR: 2.93, 95%CI: 2.29–3.75), <italic>PALB2</italic> (OR: 9.53, 95%CI: 6.25–14.51), and <italic>TP53</italic> (OR: 7.30, 95%CI: 1.22–43.68). <italic>NBN</italic> germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73–2.64). Due to their low mutation prevalence, the <italic>RAD51C</italic> and <italic>RAD51D</italic> genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in <italic>CHEK2</italic> and <italic>TP53</italic> in BC index patients. Compared with the overall sample, only <italic>TP53</italic> mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the <italic>CHEK2</italic>,<italic> PALB2,</italic> and <italic>TP53</italic> genes with bilateral BC. Both, <italic>ATM</italic> and <italic>CHEK2</italic>, were negatively associated with triple‐negative breast cancer (TNBC) and estrogen receptor (ER)‐negative tumor phenotypes. A particularly high <italic>CHEK2</italic> mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)‐positive tumors. [ABSTRACT FROM AUTHOR]