Classification of Variants of Reduced Penetrance in High Penetrance Cancer Susceptibility Genes: Framework for Genetics Clinicians and Clinical Scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK).

Autor:	Garrett A; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; St George's University Hospitals NHS Foundation Trust, Tooting, London, UK., Allen S; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK., Durkie M; Sheffield Diagnostic Genetics Service, NEY Genomic Laboratory Hub, Sheffield Children's NHS Foundation Trust, Sheffield, UK., Burghel GJ; Manchester Centre for Genomic Medicine and NW Laboratory Genetics Hub, Manchester University Hospitals NHS Foundation Trust, Manchester, UK., Robinson R; The Leeds Genetics Laboratory, NEY Genomic Laboratory Hub, Leeds Teaching Hospitals NHS Trust, Leeds, UK., Callaway A; Central and South Genomics Laboratory Hub, Wessex Genomics Laboratory Service, University Hospital Southampton NHS Foundation Trust, Salisbury, UK., Field J; Genomics and Molecular Medicine Service, Nottingham University Hospitals NHS Trust, Nottingham, UK., Frugtniet B; St George's University Hospitals NHS Foundation Trust, Tooting, London, UK., Palmer-Smith S; Institute of Medical Genetics, University Hospital of Wales, Cardiff and Vale University Health Board, Cardiff, UK., Grant J; Laboratory Genetics, Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK., Pagan J; South East Scotland Clinical Genetics, Western General Hospital, Edinburgh, UK., McDevitt T; Department of Clinical Genetics, CHI at Crumlin, Dublin, Ireland., Rowlands CF; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK., McVeigh T; The Royal Marsden NHS Foundation Trust, Fulham Road, London., Hanson H; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Peninsula Regional Genetics Service, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK; Faculty of Health and Life Sciences, University of Exeter, Exeter, UK., Turnbull C; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, Fulham Road, London. Electronic address: Turnbull.lab@icr.ac.uk.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2024 Oct 24, pp. 101305. Date of Electronic Publication: 2024 Oct 24.
DOI:	10.1016/j.gim.2024.101305
Abstrakt:	Purpose: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene (CSG) as though having equivalent penetrance, despite increasing evidence of inter-variant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants where reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance (VUS). We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network. Methods: A series of surveys and live polls were conducted during and between CanVIG-UK monthly meetings on various scenarios potentially indicating reduced penetrance. These informed the iterative development of a framework for the classification of variants of reduced penetrance by the CanVIG-UK Steering and Advisory Group (CStAG) working group. Results: CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants where (A) Active evidence suggests a reduced penetrance effect size (e.g. from case-control or segregation data) (B) Reduced penetrance effect is inferred from weaker/potentially-inconsistent observed data. Conclusions: CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, whilst developed for CSGs, are potentially applicable to other clinical contexts. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
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