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Validating data from multiplex assays of variant effect: a CanVIG-UK national survey of NHS clinical scientists

Allen, S.
; 
Garrett, A.
; 
Rowlands, C. F.
; 
Durkie, M.
; 
Burghel, G. J.
; 
Robinson, R.
; 
Callaway, A.
; 
Field, J.
; 
Frugtniet, B.
; 
Palmer-Smith, S.
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Abstract
Advances in technology have made it possible for multiplex assays of variant effect (MAVEs) to systematically generate functional data for thousands of genetic variants. Robust clinical validation and accessible online resources for MAVE data have previously been identified as barriers to the clinical adoption of new MAVEs. We delivered a survey during the November 2024 Cancer Variant Interpretation Group UK (CanVIG-UK) meeting comprising National Health Service (NHS) clinical scientists and clinical geneticists and received 46 responses from individuals regularly performing variant classification for diagnostic reporting. Only 35% reported they would accept clinical validation of the MAVE provided by the authors who conducted the assay; 20% reported they would attempt clinical validation themselves, and 61% would await clinical validation by a trusted central body. 72% reported they would use MAVE data ahead of a formal peer-reviewed publication if reviewed and clinically validated by a trusted central body. When scoring central bodies on a scale of 1-5 for confidence in their review and validation of MAVEs, CanVIG-UK (median = 5), variant curation expert panels (VCEPs; median = 5), and ClinGen SVI Functional Working Group (median = 4) all scored highly. Participants supported making variant-level data accessible via a relevant web resource (although the majority of participants expressed that additional assay-level or variant-level information would have a low likelihood of altering validation scores provided by a trusted central body). These findings, from a comparatively homogeneous clinical diagnostic group operating in a resource-constrained healthcare setting, indicate that clinical application of new MAVEs for variant classification will be delayed unless robust clinical validations are performed by a trusted central body and made readily accessible.
Authors
Allen, S.
Garrett, A.
Rowlands, C. F.
Durkie, M.
Burghel, G. J.
Robinson, R.
Callaway, A.
Field, J.
Frugtniet, B.
Palmer-Smith, S.
Grant, J.
Pagan, J.
McDevitt, T.
Snape, K.
Hanson, H.
McVeigh, T.
Adams, D. J.
Findlay, G. M.
Villani, R. M.
Spurdle, A. B.
Turnbull, C.
Affiliation
Division of Genetics and Epidemiology, the Institute of Cancer Research, London, UK. Division of Genetics and Epidemiology, the Institute of Cancer Research, London, UK; St George's University Hospitals NHS Foundation Trust, Tooting, London, UK. North East and Yorkshire Genomic Laboratory Hub, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK. Manchester Centre for Genomic Medicine and NW Laboratory Genetics Hub, Manchester University Hospitals NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, the University of Manchester, Manchester, UK. Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK. Central and South Genomics Laboratory Hub, Wessex Genomics Laboratory Service, University Hospital Southampton NHS Foundation Trust, Salisbury, UK. Genomics and Molecular Medicine Service, Nottingham University Hospitals NHS Trust, Nottingham, UK. St George's University Hospitals NHS Foundation Trust, Tooting, London, UK. Wales Genomic Health Centre, Cardiff and Vale University Health Board, Cardiff, UK. Laboratory Genetics, Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK. South East Scotland Clinical Genetics, Western General Hospital, Edinburgh, UK. Department of Clinical Genetics, Children's Health Ireland at Crumlin, Dublin, Ireland. Peninsula Regional Genetics Service, Royal Devon University Healthcare National Health Service Foundation Trust, Exeter, UK; Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK. The Royal Marsden National Health Service Foundation Trust, Fulham Road, London, UK. Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. The Genome Function Laboratory, the Francis Crick Institute, London, UK. QIMR Berghofer, Brisbane, QLD, Australia. QIMR Berghofer, Brisbane, QLD, Australia; University of Queensland, Brisbane, QLD, Australia. Division of Genetics and Epidemiology, the Institute of Cancer Research, London, UK; The Royal Marsden National Health Service Foundation Trust, Fulham Road, London, UK. Electronic address: turnbull.lab@icr.ac.uk.
Description
Date
2025
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All Paterson Institute for Cancer Research
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Citation
Allen S, Garrett A, Rowlands CF, Durkie M, Burghel GJ, Robinson R, et al. Validating data from multiplex assays of variant effect: A CanVIG-UK national survey of NHS clinical scientists. American journal of human genetics. 2025 Jun 5;112(6):1479-88. PubMed PMID: 40480200. Pubmed Central PMCID: PMC12256791. Epub 2025/06/07. eng.
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https://christie.openrepository.com/handle/10541/628240
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