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Combining evidence for and against pathogenicity for variants in cancer susceptibility genes: CanVIG-UK consensus recommendations
  1. Alice Garrett1,
  2. Miranda Durkie2,
  3. Alison Callaway3,4,
  4. George J Burghel5,
  5. Rachel Robinson6,
  6. James Drummond7,
  7. Bethany Torr1,
  8. Cankut Cubuk1,
  9. Ian R Berry6,
  10. Andrew J Wallace5,
  11. Sian Ellard8,
  12. Diana M Eccles9,
  13. Marc Tischkowitz10,
  14. Helen Hanson11,
  15. Clare Turnbull1,12
  16. CanVIG-UK
    1. 1Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, London, UK
    2. 2Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
    3. 3Wessex Regional Genetics Laboratory, Salisbury Hospital NHS Foundation Trust, Salisbury, Wiltshire, UK
    4. 4Human Genetics and Genomic Medicine, University of Southampton Faculty of Medicine, Southampton, UK
    5. 5Manchester Centre for Genomic Medicine and NW Laboratory Genetics Hub, Manchester University NHS Foundation Trust, Manchester, UK
    6. 6Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK
    7. 7East Anglian Medical Genetics Service, Addenbrooke’s Hospital, Cambridge, Cambridgeshire, UK
    8. 8Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, UK
    9. 9Cancer Sciences Research Group, University of Southampton Faculty of Medicine, Southampton, UK
    10. 10Department of Medical Genetics and National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, Cambridgeshire, UK
    11. 11Department of Clinical Genetics, St George's University Hospitals NHS Foundation Trust, London, UK
    12. 12Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK
    1. Correspondence to Dr Clare Turnbull, Cancer Genetics, Institute of Cancer Research Division of Genetics and Epidemiology, Sutton SM2 5NG, London, UK; clare.turnbull{at}


    Accurate classification of variants in cancer susceptibility genes (CSGs) is key for correct estimation of cancer risk and management of patients. Consistency in the weighting assigned to individual elements of evidence has been much improved by the American College of Medical Genetics (ACMG) 2015 framework for variant classification, UK Association for Clinical Genomic Science (UK-ACGS) Best Practice Guidelines and subsequent Cancer Variant Interpretation Group UK (CanVIG-UK) consensus specification for CSGs. However, considerable inconsistency persists regarding practice in the combination of evidence elements. CanVIG-UK is a national subspecialist multidisciplinary network for cancer susceptibility genomic variant interpretation, comprising clinical scientist and clinical geneticist representation from each of the 25 diagnostic laboratories/clinical genetic units across the UK and Republic of Ireland. Here, we summarise the aggregated evidence elements and combinations possible within different variant classification schemata currently employed for CSGs (ACMG, UK-ACGS, CanVIG-UK and ClinGen gene-specific guidance for PTEN, TP53 and CDH1). We present consensus recommendations from CanVIG-UK regarding (1) consistent scoring for combinations of evidence elements using a validated numerical ‘exponent score’ (2) new combinations of evidence elements constituting likely pathogenic’ and ‘pathogenic’ classification categories, (3) which evidence elements can and cannot be used in combination for specific variant types and (4) classification of variants for which there are evidence elements for both pathogenicity and benignity.

    • genetics
    • genomics
    • genetic testing
    • genetics
    • medical
    • genetic variation

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    • Twitter @BurghelG, @LaughingGenome, @clare__turnbull

    • AG, MD and AC contributed equally.

    • Collaborators CanVIG-UK: Stephen Abbs, Patrick Tarpey, Jonathan Bruty, James Drummond, James Whitworth, Anne Ramsay Bowden, Marc Tischowitz, Eamonn Maher (Cambridge University Hospitals NHS Foundation Trust); Shirley Heggarty, Sean Hegarty, Rosalind Martin, Peter Logan, Claire Byrne (Belfast Health and Social Care Trust); Yvonne Wallis, Samantha Butler, Rachel Hart, Lowri Hughes, Kim Reay, Kai-Ren Ong, Joanne Mason, Ian Tomlinson (Birmingham Women’s and Children’s NHS Foundation Trust); Ian Frayling, Sheila Palmer-Smith, Julian Sampson, Alex Murray (Cardiff and Vale University Health Board); Munaza Ahmed, Louise Kiely, Louise Busby, Claire Brooks, Alison Taylor-Beadling, Ajith Kumar (Great Ormond Street Hospital for Children NHS Foundation Trust); Vishakha Tripathi, Mina Ryten, Louise Izatt, Anjana Kulkarni, Adam Shaw, Joanna Campbell (Guy’s and St Thomas’ NHS Foundation Trust); Huw Thomas (St. Mark’s Hospital, Northwick Park Hospital, Harrow); Daniel Chubb, Bethany Torr, Cankut Cubuk (Institute of Cancer Research); Rachel Robinson, Brendan Mullaney, Julian Adlard (Leeds Teaching Hospitals NHS Trust); Karen-Lynn Greenhalgh, Emma Howard (Liverpool Women’s NHS Foundation Trust); Virginia Clowes, Angela Brady (London North West University Healthcare NHS Trust); George Burghel, Emma Woodward, Philip T Smith, Jade L Harris, Naomi L Bowers, Claire L Hartley, Ronnie Wright, Gareth Evans, Fiona Lalloo, Andrew Wallace (Manchester University NHS Foundation Trust); John Burn, James Tellez, Sarah Mackenzie, Helen Powell (Newcastle Upon Tyne Hospitals NHS Foundation Trust); Stephen Tennant, Joanna Tolmie, Dawn O’Sullivan (NHS Grampian, Aberdeen); Rosemarie Davidson, Jonathan Grant, Daniel Stobo, Aisha Ansari (NHS Greater Glasgow Jennie Murray, David Moore (NHS Lothian, Edinburgh); Rachael Tredwell, Joanne Field, Kirsty Bradshaw, Rachel Harrison (Nottingham University Hospital NHS Trust); Logan Walker (University of Otago, Christchurch, New Zealand); Trudi Mcdevitt, Marie Duff, Catherine Clabby (Our Lady’s Children’s Hospital, Crumlin, Dublin); Treena Cranston, Tina Bedenham, Evgenia Petrides, Lara Hawkes (Oxford University Hospitals NHS Foundation Trust); Fiona McRonald (Public Health England); Sian Ellard, Ruth Cleaver, Carole Brewer (Royal Devon And Exeter NHS Foundation Trust); Nick Woodwaer (Royal Free London NHS Foundation Trust); Stacey Daniels, Alison Callaway (Salisbury NHS Foundation Trust); Khalid Tobal, Shadi Albaba, Sarah Dell, Rodney Nyanhete, Richard Kirk, Mark Watson, Miranda Durkie, Jackie Cook, Hazel Clouston, Anne-Cecile Hogg (Sheffield Children’s NHS Foundation Trust); Sabrina Talukdar, Lorraine Hawkes, Laura Cobbold, Kate Tatton-Brown, Helen Hanson, Katie Snape, Charlene Crosby, Ayaovi Hadonou Juan Carlos Del Rey Jimenez(St George’s University Hospitals NHS Foundation Trust); Zoe Kemp, Terri Mcveigh, Clare Turnbull, Alice Garrett (The Royal Marsden NHS Foundation Trust); Cathal O’Brien (Trinity College Dublin, The University Of Dublin, Ireland); Laura Yarram, Kenneth Smith, Helen Williamson, Alan Donaldson (University Hospitals Bristol NHS Foundation Trust); Julian Barwell (University Hospitals of Leicester NHS Trust); Matilda Bradford (University Hospitals Plymouth NHS Trust); Lucy Side, Diana Eccles, Diana Baralle, Anneke Lucassen (University Hospital Southampton NHS Foundation Trust).

    • Contributors The manuscript was drafted by CT, AG, AC and MD. All other authors contributed to the final manuscript.

    • Funding This work is supported by the CRUK Catalyst Award CanGene-CanVar (C61296/A27223).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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