Background While the requirement for thresholds for testing for mutations in BRCA1/2 is being questioned, they are likely to remain for individuals unaffected by a relevant cancer. It is still useful to provide pretesting likelihoods, but models need to take into account tumour pathology.
Methods The Manchester Scoring System (MSS) is a well-used, simple, paper-based model for assessing carrier probability that already incorporates pathology data. We have used mutation testing data from 4115 unrelated samples from affected non-Jewish individuals alongside tumour pathology to further refine the scoring system.
Results Adding additional points for high-grade serous ovarian cancer <60 (HGSOC=+2) and adding grade score to those with triple-negative breast cancer, while reducing the score for those with HER2+ breast cancer (−6), resulted in significantly improved sensitivity and minor improvements in specificity to the MSS. Sporadic HGSOC <60 years thus reached a score of 15–19 points within the 10% grouping consistent with the 15/113–13.2% that were identified with a BRCA1/2 pathogenic variant. Validation in a population series of ovarian cancer from Cambridge showed high sensitivity at the 10% threshold 15/17 (88.2%).
Conclusions The new pathology-adjusted Manchester score MSS3 appears to provide an effective and simple-to-use estimate of the 10% and 20% thresholds for BRCA1/2 likelihood. For unaffected individuals, the 20-point (20%) threshold in their affected first-degree relative can be used to determine eligibility at the 10% threshold.
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Contributors Concept: DGE.
Data acquisition: DGE, FL, ERW, MT, IP and TAH.
Data analysis: DGE, EFH and IP.
Manuscript writing: all.
Final version acceptance: all.
Funding We acknowledge the support of the National Institute for Health Research (NIHR) and the Genesis Prevention Appeal for their funding. DGE is an NIHR senior investigator.
Competing interests None declared.
Ethics approval North Manchester REC.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Raw data are available on request.
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