Population-based germline testing of , and in breast cancer patients in the United Kingdom: 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 , , and Partner and Localiser of BRCA2 (). 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 ( = 9  = 18 = 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.