首页|Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants

Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants

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  • NSTL
  • Elsevier
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. (C) 2021 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.

ACMGClassificationCodonPM5VariantSEQUENCESUBSTITUTIONSGUIDELINESMATRICESRISK

Loong, Lucy、Cubuk, Cankut、Choi, Subin、Allen, Sophie、Torr, Beth、Garrett, Alice、Loveday, Chey、Durkie, Miranda、Callaway, Alison、Burghel, George J.、Drummond, James、Robinson, Rachel、Berry, Ian R.、Wallace, Andrew、Eccles, Diana M.、Tischkowitz, Marc、Ellard, Sian、Ware, James S.、Hanson, Helen、Turnbull, Clare、CanVIG-UK

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Div Genet & Epidemiol,Inst Canc Res

Sheffield Diagnost Genet Serv,Sheffield Childrens NHS Fdn Trust

Wessex Reg Genet Lab,Salisbury NHS Fdn Trust

Manchester Ctr Genom Med,Manchester Univ NHS Fdn Trust

Cambridge Univ Hosp Genom Lab,Cambridge Univ Hosp NHS Fdn Trust

North East & Yorkshire Genom Lab Hub,Leeds Teaching Hosp NHS Trust

Southmead Hosp,North Bristol NHS Trust

Fac Med,Univ Southampton

Dept Med Genet,Univ Cambridge

Dept Mol Genet,Royal Devon & Exeter NHS Fdn Trust

Fac Med,Imperial Coll London

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2022

10.1016/j.gim.2021.11.011

Genetics in medicine

Genetics in medicine

ISTP
ISSN：1098-3600
年,卷(期)：2022.24(3)
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