Combining evidence for and against pathogenicity for variants in cancer susceptibility genes: CanVIG-UK consensus recommendations. Issue 5 (18th November 2020)

• Record Type: Journal Article
• Authors: Garrett, Alice; Durkie, Miranda; Callaway, Alison; Burghel, George J; Robinson, Rachel; Drummond, James; Torr, Bethany; Cubuk, Cankut; Berry, Ian R; Wallace, Andrew J; Ellard, Sian; Eccles, Diana M; Tischkowitz, Marc; Hanson, Helen; Turnbull, Clare
• Other Names: author non-byline.; Abbs Stephen author non-byline.; Tarpey Patrick author non-byline.; Bruty Jonathan author non-byline.; Drummond James author non-byline.; Whitworth James author non-byline.; Bowden Anne Ramsay author non-byline.; Tischowitz Marc author non-byline.; Maher Eamonn author non-byline.; Heggarty Shirley author non-byline.; Hegarty Sean author non-byline.; Martin Rosalind author non-byline.; Logan Peter author non-byline.; Byrne Claire author non-byline.; Wallis Yvonne author non-byline.; Butler Samantha author non-byline.; Hart Rachel author non-byline.; Hughes Lowri author non-byline.; Reay Kim author non-byline.; Ong Kai-Ren author non-byline.; Mason Joanne author non-byline.; Tomlinson Ian author non-byline.; Frayling Ian author non-byline.; Palmer-Smith Sheila author non-byline.; Sampson Julian author non-byline.; Murray Alex author non-byline.; Ahmed Munaza author non-byline.; Kiely Louise author non-byline.; Busby Louise author non-byline.; Brooks Claire author non-byline.; Taylor-Beadling Alison author non-byline.; Kumar Ajith author non-byline.; Tripathi Vishakha author non-byline.; Ryten Mina author non-byline.; Izatt Louise author non-byline.; Kulkarni Anjana author non-byline.; Shaw Adam author non-byline.; Campbell Joanna author non-byline.; Thomas Huw author non-byline.; Chubb Daniel author non-byline.; Torr Bethany author non-byline.; Cubuk Cankut author non-byline.; Robinson Rachel author non-byline.; Mullaney Brendan author non-byline.; Adlard Julian author non-byline.; Greenhalgh Karen-Lynn author non-byline.; Howard Emma author non-byline.; Clowes Virginia author non-byline.; Brady Angela author non-byline.; Burghel George author non-byline.; Woodward Emma author non-byline.; Smith Philip T author non-byline.; Harris Jade L author non-byline.; Bowers Naomi L author non-byline.; Hartley Claire L author non-byline.; Wright Ronnie author non-byline.; Evans Gareth author non-byline.; Lalloo Fiona author non-byline.; Wallace Andrew author non-byline.; Burn John author non-byline.; Tellez James author non-byline.; Mackenzie Sarah author non-byline.; Powell Helen author non-byline.; Tennant Stephen author non-byline.; Tolmie Joanna author non-byline.; O'Sullivan Dawn author non-byline.; Davidson Rosemarie author non-byline.; Grant Jonathan author non-byline.; Stobo Daniel author non-byline.; Ansari Aisha author non-byline.; Tredwell Rachael author non-byline.; Field Joanne author non-byline.; Bradshaw Kirsty author non-byline.; Harrison Rachel author non-byline.; Walker Logan author non-byline.; Mcdevitt Trudi author non-byline.; Duff Marie author non-byline.; Clabby Catherine author non-byline.; Cranston Treena author non-byline.; Bedenham Tina author non-byline.; Petrides Evgenia author non-byline.; Hawkes Lara author non-byline.; McRonald Fiona author non-byline.; Ellard Sian author non-byline.; Cleaver Ruth author non-byline.; Brewer Carole author non-byline.; Woodwaer Nick author non-byline.; Daniels Stacey author non-byline.; Callaway Alison author non-byline.; Tobal Khalid author non-byline.; Albaba Shadi author non-byline.; Dell Sarah author non-byline.; Nyanhete Rodney author non-byline.; Kirk Richard author non-byline.; Watson Mark author non-byline.; Durkie Miranda author non-byline.; Cook Jackie author non-byline.; Clouston Hazel author non-byline.; Hogg Anne-Cecile author non-byline.; Talukdar Sabrina author non-byline.; Hawkes Lorraine author non-byline.; Cobbold Laura author non-byline.; Tatton-Brown Kate author non-byline.; Hanson Helen author non-byline.; Snape Katie author non-byline.; Crosby Charlene author non-byline.; Jimenez Ayaovi author non-byline.; Kemp Zoe author non-byline.; Mcveigh Terri author non-byline.; Turnbull Clare author non-byline.; Garrett Alice author non-byline.; O'Brien Cathal author non-byline.; Yarram Laura author non-byline.; Smith Kenneth author non-byline.; Williamson Helen author non-byline.; Donaldson Alan author non-byline.; Barwell Julian author non-byline.; Bradford Matilda author non-byline.; Side Lucy author non-byline.; Eccles Diana author non-byline.; Baralle Diana author non-byline.; Lucassen Anneke author non-byline.;
• Is Part Of: Journal of medical genetics. Volume 58:Issue 5(2021)
• Page Start: 297
• Page End: 304
• Publication Date: 2020-11-18
• Subjects: genetics -- genomics -- genetic testing -- genetics -- medical -- genetic variation; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2020-107248
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : 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.