RT Journal Article SR Electronic T1 Pathology update to the Manchester Scoring System based on testing in over 4000 families JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2017-104584 DO 10.1136/jmedgenet-2017-104584 A1 D Gareth Evans A1 Elaine F Harkness A1 Inga Plaskocinska A1 Andrew J Wallace A1 Tara Clancy A1 Emma R Woodward A1 Tony A Howell A1 Marc Tischkowitz A1 Fiona Lalloo YR 2017 UL http://jmg.bmj.com/content/early/2017/05/10/jmedgenet-2017-104584.abstract AB 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.