{
  "abstract": "Background Genetic testing for (likely) pathogenic variants (PVs) in BRCA1/BRCA2 has been performed in Manchester since 1996, with molecular methods/techniques and eligibility criteria changing over time. In 2004, UK National Institute for Health and Care Excellence guidelines determined a 20% detection threshold, which reduced to 10% in 2013. The Manchester score (MS) was developed in 2004 to assess the likelihood of detecting PVs at the 10%/20% threshold and was updated to include pathology adjustment (2009/17). Current testing algorithms for NHS England are now closer to 5%, although an MS of 15 (=10%) and CanRisk of 10% are still backstop indications. We provide an update of MS on testing of nearly 10 000 breast and/or ovarian cancer (BC/OC) cases.Methods MS using pathology adjustment was applied to cases of non-Jewish BC/OC cases undergoing full screening of BRCA1/2 with testing for CNVs.Results Overall, 6744 BC and 3291 OC cases were tested. For BC, 453 (6.7%) PVs were detected in BRCA1 and 456 (6.8%) in BRCA2 (combined 13.5%). Combined detection with MS=13–14, 15–19 and 20–24 was 52/821 (6.3%), 168/1440 (11.7%) and 193/877 (22.0%), respectively. The MS 15–19 (10%) threshold held true for all age groups and BC pathology types, except grade 1 (very low detection). For OC, detection rates were 273 (8.3%) and 193 (5.9%) for BRCA1 and BRCA2, respectively. Again, the 10%/20% threshold MS held true with MS=15–19=123/861 (14.3%) and 13–14=22/301 (7.3%). MS=11 gave a robust 5% threshold, although only 1/86 (1.2%) OC <30 years tested positive; this was 1/5 high-grade serous cancers. For sporadic OC >79 years, only 2/177 (1.1%) tested positive.Conclusions MS remains a robust algorithm for assessing likelihood of a BRCA1/BRCA2 PV for individuals with BC/OC.",
  "authors": [
    {
      "affiliations": [
        "Genomic Medicine, University of Manchester - The Victoria University of Manchester Campus, Manchester, UK",
        "Genomic Diagnostic Laboratory, Manchester University NHS Foundation Trust, Manchester, UK"
      ],
      "name": "D Gareth Evans"
    },
    {
      "affiliations": [
        "Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK",
        "cancer studies, University of Manchester, Manchester, UK"
      ],
      "name": "Robert D Morgan"
    },
    {
      "affiliations": [
        "Clinical Genetics Service, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK"
      ],
      "name": "Claire Forde"
    },
    {
      "affiliations": [
        "Division of Molecular and Clinical Cancer Sciences, The University of Manchester, Manchester, UK",
        "University of Manchester, Manchester, UK"
      ],
      "name": "Emma J Crosbie"
    },
    {
      "affiliations": [
        "Genomic Diagnostic Laboratory, Manchester University NHS Foundation Trust, Manchester, UK"
      ],
      "name": "George J Burghel"
    },
    {
      "affiliations": [
        "Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK"
      ],
      "name": "Sarah Pugh"
    },
    {
      "affiliations": [
        "Prevent Breast Cancer Centre, Wythenshawe Hospital Manchester Universities Foundation Trust, Wythenshawe, UK"
      ],
      "name": "Ashu Gandhi"
    },
    {
      "affiliations": [
        "Prevent Breast Cancer Centre, Manchester, UK"
      ],
      "name": "Anthony Howell"
    },
    {
      "affiliations": [
        "Wythenshawe Hospital Manchester Universities Foundation Trust, Wythenshawe, UK",
        "The Christie NHS Foundation Trust, Manchester, UK"
      ],
      "name": "Sacha J Howell"
    },
    {
      "affiliations": [
        "Manchester Centre for Genomic Medicine, Central Manchester NHS Foundation Trust, Manchester, UK"
      ],
      "name": "Emma Roisin Woodward"
    },
    {
      "affiliations": [
        "Clinical Genetics Service, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK"
      ],
      "name": "Fiona Lalloo"
    }
  ],
  "title": "Validation of the pathology-adjusted Manchester scoring system in over 10 000 assessments of cases with breast and/or ovarian cancer",
  "uid": "839635d0-4ed1-5f6a-8119-f18a54969ea7"
}