Pathology update to the Manchester Scoring System based on testing in over 4000 families

Background: Whilst 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 pre-testing likelihoods, but models need to take into account tumour pathology.Methods: The Manchester scoring system (MSS) is a well utilised, 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, whilst 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.