Population based germline testing of BRCA1, BRCA2 and PALB2 in breast cancer patients in the UK: evidence to support extended testing and definition of groups who may not require testing

Purpose To assess the contribution of germline pathogenic variants (PVs) in population-based series of breast cancers and the best strategy to improve detection rates. Methods Three cohort studies were utilized, including a hospital-based series identified from new UK mainstream testing criteria (group-1), offering testing to all women (group-2-BReast CAncer [BRCA]-DIRECT), and a Greater Manchester cohort study recruited from the mammography screening population (group-3-Predicting Risk of Cancer at Screening). DNA samples from women with breast cancer were sequenced for PVs in BRCA1, BRCA2, and Partner and Localiser of BRCA2 (PALB2). The Manchester score (MS) was used at different points thresholds. Current mainstream criteria include women diagnosed <40 years and all triple negative <60 years or an MS ≥15. Results Thirty-six PVs (BRCA1 = 9, BRCA2 = 18, PALB2 = 9) were identified among 1061 women with breast cancer (3.4%). Mainstreaming criteria identified 21 of 36 (58%) of PVs by testing 190 women; detection rate (8.4%), specificity = 83.5%. A better detection rate was found using an MS threshold of 12-points with 66.7% (24/36) sensitivity and 85.7% specificity in 171 women. No PVs were identified in 158 women with grade-1 invasive cancers. The best strategy to detect all PVs was an MS ≥3 with specificity of 32.6%. Conclusion In order to detect higher PV rates on a population basis the best strategy is to reduce the MS threshold for genetic testing.