Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants
Lucy Loong, Cankut Çubuk, Subin Choi, Sophie Allen, Beth Torr, Alice Garrett, Chey Loveday, Miranda Durkie, Alison Callaway, George J. Burghel, James Drummond, Rachel Robinson, Ian Berry, Andrew J. Wallace, Diana M. Eccles, Marc Tischkowitz, Sian Ellard, James S. Ware, Helen Hanson, Clare Turnbull, Shalaka Samant, Anneke Lucassen, Anna Znaczko, Adam Shaw, Azhar Ansari, Ashis Kumar, Alan Donaldson, Anne R. Murray, Alison Ross, Alison Taylor‐Beadling, Algy Taylor, A. Micheil Innes, Angie Brady, A. Kulkarni, Andrew C. Hogg, A. Ramsay Bowden, A. M. Hadonou, Brian W. Coad, Beth McIldowie, Beverley Speight, Bianca DeSouza, Brendan Mullaney, Caoimhe McKenna, Carmen C. Brewer, Catarina Olimpio, Catherine Clabby, Andrew H. Crosby, Charisma L. Jenkins, Christine Armstrong, Christopher Bowles, Claire Brooks, C Byrne, Constance Maurer, Diana Baralle, Daniel Chubb, Daniel Stobo, David Moore, D. O'Sullivan, Dan Donnelly, D. Randhawa, Dorothy Halliday, Eric A. Atkinson, Emma L. Baple, E. Rauter, Emma Johnston, Emma R. Woodward, E.R. Maher, Eleni Sofianopoulou, Evgenia Petrides, Fiona Lalloo, Fiona E. McRonald, F. Pelz, Ian M. Frayling, D. Gareth Evans, G. Corbett, Gillian Rea, Hazel Clouston, Helen Powell, Hobart R. Williamson, Helena Carley, Huw Thomas, Ian Tomlinson, James M. Cook, Jacqueline Hoyle, James O. Tellez, James W. Whitworth, Jonathan Williams, JM Murray, Johnathan W. Campbell, John Tolmie, John K. Field, Joanne Mason, John Burn, Jonathan Bruty, Jonathan L A Callaway, Jacob D Grant, JC Del Rey Jimenez, José A Pagán, Jake VanCampen, Julian Barwell
Abstract
PURPOSE: Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice. METHODS: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset. RESULTS: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62. CONCLUSION: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met.