Clinical likelihood ratios and balanced accuracy for 44 in silico tools against multiple large-scale functional assays of cancer susceptibility genes

Clinical likelihood ratios and balanced accuracy for 44 in silico tools against multiple large-scale functional assays of cancer susceptibility genes

Purpose Where multiple in silico tools are concordant, the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) framework affords supporting evidence toward pathogenicity or benignity, equivalent to a likelihood ratio of ~2. However, limited availability o...

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Veröffentlicht in:Genetics in medicine 2021-11, Vol.23 (11), p.2096-2104
Hauptverfasser: Cubuk, C., Garrett, A., Choi, S., King, L., Loveday, C., Torr, B., Burghel, G. J., Durkie, M., Callaway, A., Robinson, R., Drummond, J., Berry, I., Wallace, A., Eccles, D., Tischkowitz, M., Whiffin, N., Ware, J. S., Hanson, H., Turnbull, C., CanVIG-UK
Format: Artikel
Sprache:eng
Schlagworte:
Accuracy
Algorithms
Amino acids
Binding sites
Biomedical and Life Sciences
Biomedicine
Cancer
Computer Simulation
Datasets
Disease
Genes
Genetic Variation
Genetics
Genomes
Genomics
Hospitals
Human Genetics
Humans
Laboratories
Laboratory Medicine
Medical research
Medicine
Mutation, Missense
Neoplasms - diagnosis
Neoplasms - genetics
NMR
Nuclear magnetic resonance
Proteins
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Zusammenfassung:Purpose Where multiple in silico tools are concordant, the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) framework affords supporting evidence toward pathogenicity or benignity, equivalent to a likelihood ratio of ~2. However, limited availability of “clinical truth sets” and prior use in tool training limits their utility for evaluation of tool performance. Methods We created a truth set of 9,436 missense variants classified as deleterious or tolerated in clinically validated high-throughput functional assays for BRCA1 , BRCA2 , MSH2 , PTEN , and TP53 to evaluate predictive performance for 44 recommended/commonly used in silico tools. Results Over two-thirds of the tool–threshold combinations examined had specificity of
ISSN:1098-3600
1530-0366
DOI:10.1038/s41436-021-01265-z