Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria

Recommendations from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) for interpreting sequence variants specify the use of computational predictors as "supporting" level of evidence for pathogenicity or benignity using criteria PP3 and BP4, respectively. However, score intervals defined by tool developers, and ACMG/AMP recommendations that require the consensus of multiple predictors, lack quantitative support. Previously, we described a probabilistic framework that quantified the strengths of evidence (supporting, moderate, strong, very strong) within ACMG/AMP recommendations. We have extended this framework to computational predictors and introduce…

• P
  Pfizer
• A
  AstraZeneca
• NI
  National Institutes of Health

  Awards: R01 CA264971, U24 HG011450, U24 HG006834, U24 HG007346, R01 CA121245, U24 CA258119, U41 HG009649, U01 HG012022, R13 HG006650, ZI AHG200359, K99 LM012992, U01 HG011755, UM1 HG008900
• NH
  National Human Genome Research Institute
• NC
  National Cancer Institute

  Award: U24 HG009650