title: M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity.
abstract: Variant pathogenicity classifiers such as SIFT, PolyPhen-2, CADD, and MetaLR assist in interpretation of the hundreds of rare, missense variants in the typical patient genome by deprioritizing some variants as likely benign. These widely used methods misclassify 26 to 38% of known pathogenic mutations, which could lead to missed diagnoses if the classifiers are trusted as definitive in a clinical setting. We developed M-CAP, a clinical pathogenicity classifier that outperforms existing methods at all thresholds and correctly dismisses 60% of rare, missense variants of uncertain significance in a typical genome at 95% sensitivity.
authors: Department of Computer Science, Stanford University, Stanford, California, USA.
authors: Karthik A
authors: KA
authors: Jagadeesh
authors: Department of Pediatrics, Stanford University, Stanford, California, USA.
authors: Aaron M
authors: AM
authors: Wenger
authors: Department of Computer Science, Stanford University, Stanford, California, USA.
authors: Mark J
authors: MJ
authors: Berger
authors: Department of Pediatrics, Stanford University, Stanford, California, USA.
authors: Harendra
authors: H
authors: Guturu
authors: Department of Medical Genetics, Cardiff University, Heath Park, Cardiff, UK.
authors: Peter D
authors: PD
authors: Stenson
authors: Department of Medical Genetics, Cardiff University, Heath Park, Cardiff, UK.
authors: David N
authors: 0000-0002-8943-8484
authors: DN
authors: Cooper
authors: Department of Pediatrics, Stanford University, Stanford, California, USA.
authors: Jonathan A
authors: JA
authors: Bernstein
authors: Department of Computer Science, Stanford University, Stanford, California, USA.|Department of Pediatrics, Stanford University, Stanford, California, USA.|Department of Developmental Biology, Stanford University, Stanford, California, USA.
authors: Gill
authors: G
authors: Bejerano
mesh_terms: D019295:Computational Biology / Q000379:methods*; D004252:DNA Mutational Analysis / Q000379:methods; D004194:Disease / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation / Q000235:genetics*; D011237:Predictive Value of Tests; D012984:Software
chemical_list: D005819:Genetic Markers