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Pathology update to the Manchester Scoring System based on testing in over 4000 families
  1. D Gareth Evans1,2,3,4,5,
  2. Elaine F Harkness6,
  3. Inga Plaskocinska, `7,
  4. Andrew J Wallace3,
  5. Tara Clancy3,
  6. Emma R Woodward1,3,
  7. Tony A Howell2,5,
  8. Marc Tischkowitz7,
  9. Fiona Lalloo3
  1. 1 Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester Academic Health Centre, Division of Evolution and Genomic Medicine, University of Manchester, Manchester, UK
  2. 2 Prevent Breast Cancer Prevention Centre, University Hospital of South Manchester NHS Foundation Trust, Wythenshawe, Manchester, UK
  3. 3 Manchester Centre for Genomic Medicine, St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  4. 4 Manchester Breast Centre, The Christie, Manchester, UK
  5. 5 Department of Medical Oncology, The Christie, Manchester, UK
  6. 6 Division of Informatics, Imaging and Data Sciences, University of Manchester, Manchester, UK
  7. 7 Department of Medical Genetics and National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
  1. Correspondence to Professor D Gareth Evans, Manchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, St Mary’s Hospital, University of Manchester, Manchester M13 9WL, UK; gareth.evans{at}


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.

  • BRCA1
  • BRCA2
  • Manchester Scoring System
  • pathology
  • high grade serous ovarian cancer
  • triple negative breast cancer
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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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