TY - JOUR T1 - Pathology update to the Manchester Scoring System based on testing in over 4000 families JF - Journal of Medical Genetics JO - J Med Genet SP - 674 LP - 681 DO - 10.1136/jmedgenet-2017-104584 VL - 54 IS - 10 AU - D Gareth Evans AU - Elaine F Harkness AU - Inga Plaskocinska AU - Andrew J Wallace AU - Tara Clancy AU - Emma R Woodward AU - Tony A Howell AU - Marc Tischkowitz AU - Fiona Lalloo Y1 - 2017/10/01 UR - http://jmg.bmj.com/content/54/10/674.abstract N2 - 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. ER -