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)
Year: 2024
Type: article
Abstract: PURPOSE: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. 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 working group. RESULTS: CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants in which (A) active evidence suggests a reduced-penetrance effect size (eg, from case-control or segregation data) and (B) reduced penetrance effect is inferred from weaker/potentially inconsistent observed data. CONCLUSION: CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, although developed for cancer susceptibility genes, are potentially applicable to other clinical contexts.
Source: Genetics in Medicine
Authors: Alice Garrett, Sophie Allen, Miranda Durkie, George J. Burghel, Rachel Robinson, Alison Callaway, Joanne Field, Bethan Frugtniet, Sheila Palmer-Smith, Jonathan Grant, Judith Pagan, Trudi McDevitt, Charlie F. Rowlands, Terri McVeigh, Helen Hanson, Clare Turnbull, Clare Turnbull, C. Turnbull, C. Turnbull, A. Garrett, L. Loong, S. Choi, B. Torr, S. Allen, M. Durkie, A. Callaway, J. Drummond, G.J. Burghel, R. Robinson, I.R. Berry, A.J. Wallace, D.M. Eccles, M. Tischkowitz, S. Ellard, H. Hanson, E. Baple, D.G. Evans, E. Woodward, F. Lalloo, S. Samant, A. Lucassen, A. Znaczko, A. Shaw, A. Ansari, A. Kumar, A. Donaldson, A. Murray, A. Ross, A. Taylor-Beadling, A. Taylor, A. Innes, A. Brady, A. Kulkarni, A.C. Hogg, A. Ramsay Bowden, A. Hadonou, B. Coad, B. McIldowie, B. Speight, B. DeSouza, B. Mullaney, C. McKenna, C. Brewer, C. Olimpio, C. Clabby, C. Crosby, C. Jenkins, C. Armstrong, C. Bowles, C. Brooks, C. Byrne, C. Maurer, D. Baralle, D. Chubb, D. Stobo, D. Moore, D. O'Sullivan, D. Donnelly, D. Randhawa, D. Halliday, E. Atkinson, E. Rauter, E. Johnston, E. Maher, E. Sofianopoulou, E. Petrides, F. McRonald, F. Pelz, I. Frayling, G. Corbett, G. Rea, H. Clouston, H. Powell, H. Williamson, H. Carley, H.J.W. Thomas, I. Tomlinson, J. Cook, J. Hoyle, J. Tellez, J. Whitworth, J. Williams, J. Murray, J. Campbell, J. Tolmie, J. Field, J. Mason, J. Burn, J. Bruty, J. Callaway, J. Grant, J. Del Rey Jimenez, J. Pagan, J. VanCampen, J. Barwell, K. Monahan, K. Tatton-Brown, K.R. Ong, K. Murphy, K. Andrews, K. Mokretar, K. Cadoo, K. Smith, K. Baker, K. Brown, K. Reay, K. McKay Bounford, K. Bradshaw, K. Russell, K. Stone, K. Snape, L. Crookes, L. Reed, L. Taggart, L. Yarram, L. Cobbold, L. Walker, L. Walker, L. Hawkes, L. Busby, L. Izatt, L. Kiely, L. Hughes, L. Side, L. Sarkies, K.-L. Greenhalgh, M. Shanmugasundaram, M. Duff, M. Bartlett, M. Watson, M. Owens, M. Bradford, M. Huxley, M. Slean, M. Ryten, M. Smith, M. Ahmed, N. Roberts, C. O'Brien, O. Middleton, P. Tarpey, P. Logan, P. Dean, P. May, P. Brace, R. Tredwell, R. Harrison, R. Hart, R. Kirk, R. Martin, R. Nyanhete, R. Wright, R. Martin, R. Davidson, R. Cleaver, S. Talukdar, S. Butler, J. Sampson, S. Ribeiro, S. Dell, S. Mackenzie, S. Hegarty, S. Albaba, S. McKee, S. Palmer-Smith, S. Heggarty, S. MacParland, S. Greville-Heygate, S. Daniels, S. Prapa, S. Abbs, S. Tennant, S. Hardy, S. MacMahon, T. McVeigh, T. Foo, T. Bedenham, T. Cranston, T. McDevitt, V. Clowes, V. Tripathi, V. McConnell, N. Woodwaer, Y. Wallis, Z. Kemp, G. Mullan, L. Pierson, L. Rainey, C. Joyce, A. Timbs, A.-M. Reuther, B. Frugtniet, B. DeSouza, C. Husher, C. Lawn, C. Corbett, D. Nocera-Jijon, D. Reay, E. Cross, F. Ryan, H. Lindsay, J. Oliver, J. Dring, J. Spiers, J. Harper, K. Ciucias, L. Connolly, M. Tsang, R. Brown, S. Shepherd, S. Begum, S. Daniels, T. Tadiso, T. Linton-Willoughby, H. Heppell, K. Sahan, L. Worrillow, Z. Allen, C. Watt, M. Hegarty, R. Mitchell, R. Coles, G. Nickless, E. Cojocaru, I. Doal, F. Sava, C. McCarthy, R. Jeeneea, D. Goudie, M. McConachie, S. Botosneanu, G. Kavanaugh, K. Russell, C. Sherlaw, O. Tsoulaki, C. Forde, E. Petley, A.-B. Jones, K. Oprych, S. Pryde, Z. Hyder, N. Elkhateeb, R. Braham, L. Hanington, C. Huntley, R. Irving, A. Sadan, M. Ramos, C. Elliot, D. Wren, D. Lobo, J. McLean, D. May, L. Kearney, T. Campbell, K. Asakura, L. Alwadi, R. O’Shea, J. Gabriel, L. Chiecchio, P. Bowman, L.A. Sutton, C. Walsh, V. Cloke, D. Ucanok, J. Davies, B. Pleasance, E. Maguire, A. Whaite, S. Best, S. Westbury, A. Logan, D. Navarajasegaran, A. Bench, P. Wightman, A. Cartwright, E. Higgs, J.Bott, H. Whitehouse, J. Stevens, D. Martin, J. Dunlop, S. Thomas, C. Sau, S. Farndon, N. Coleman, P. Angelini, M. Duff, H. Massey, C. Rowlands, C. Garcia-Petit, K. Gillespie, A. Alder, E. Middleton, C. Cassidy, N. Orfali, A. Webb, A. Luharia, N. Walker, J. Charlton, A. Andreou, J. Peddie, M. Khan, L. Wilkinson, H. Bezuidenhout, M. Edis, A. Callard, P. Ostrowski, P. Moverley, K. Bean, A. Dunne, A. Moleirinho, S. Waller, K. Cox, L. Greensmith, A. Brittle, N. Gossan, L. Freestone, C. Shak, T. Langford, Y. Clinch, H. Livesey, S. Borland, A. Joshi, K. Wall, A. Whitworth, A. Wilsdon, K. Edgerley, S. Pugh, N. Chrysochoidi, S. Mutch, C. McMullan, Y. Johnston, M. Muraru, A. May, R. Begum, C. Smith, R. Patel, I. Bhatnagar, A. Taylor, D. Brown, J. Willan, S. Taylor, K. Jones, K. Cox, C. Ramsden, O. Taiwo, J. Jaudzemaite, R. Sharmin, L. Young, C. O’Dubhshlaine, L. McSorley, I. Abreu Rodriguez, S. Lillis, P. Alexopoulos, E. Mortensson, L. Kingham, R. Moore, M. Kosicka-Slawinska, S. Aslam, R. Wells, A. Carter, H. Warren, E. Rolf, H. Reed, L. Pearce, D. Lock, F. Ali, A. Kolozi, N. White, D. Wood, C. Hayden
Institutions: St George's Hospital, Institute of Cancer Research, St George’s University Hospitals NHS Foundation Trust, Sheffield Children's NHS Foundation Trust, Sheffield Children's Hospital, Manchester University NHS Foundation Trust, Leeds Teaching Hospitals NHS Trust, University Hospital Southampton NHS Foundation Trust, Nottingham University Hospitals NHS Trust, Cardiff and Vale University Health Board, University Hospital of Wales, NHS Greater Glasgow and Clyde, Queen Elizabeth University Hospital, Western General Hospital, Children's Health Ireland at Crumlin, Royal Marsden NHS Foundation Trust, Royal Marsden Hospital, University of Exeter, Royal Devon & Exeter NHS Foundation Trust, Royal Devon University Healthcare NHS Foundation Trust
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,490
Funder: Cancer Research UK
Awards: G2698464496, G5174455661
OpenAlex ID: W4403712082