title: A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
abstract: We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies collected from internal and external sources. Scores were calculated by trained scientists using a quantitative framework that assigned differential weighting to these five types of data. We performed descriptive and comparative statistics on the dataset and tested interobserver concordance among the trained scientists. Private variants defined as variants found within single families (n = 5,182), were either VUS (80.5%; n = 4,169) or likely pathogenic (19.5%; n = 1,013). The remaining variants (n = 6,712) were VUS (38.4%; n = 2,577) or likely benign/benign (34.7%; n = 2,327) or likely pathogenic/pathogenic (26.9%, n = 1,808). Exact agreement between the trained scientists on the final variant score was 98.5% [95% confidence interval (CI) (98.0, 98.9)] with an interobserver consistency of 97% [95% CI (91.5, 99.4)]. Variant scores were stable and showed increasing odds of being in agreement with new data when re-evaluated periodically. This carefully curated, standardized variant pathogenicity scoring system provides reliable pathogenicity scores for DNA variants encountered in a clinical laboratory setting.
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Izabela
authors.initials: I
authors.lastname: Karbassi
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Maston
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Angela
authors.initials: A
authors.lastname: Love
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Christina
authors.initials: C
authors.lastname: DiVincenzo
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Corey D
authors.initials: CD
authors.lastname: Braastad
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Elzinga
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Alison R
authors.initials: AR
authors.lastname: Bright
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Domenic
authors.initials: D
authors.lastname: Previte
authors.affiliation: Quest Diagnostics, Nichols Institute, San Juan Capistrano, California.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Quest Diagnostics, Celera, Alameda, California.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rowland
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Michele
authors.initials: M
authors.lastname: McCarthy
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Lapierre
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Felicita
authors.initials: F
authors.lastname: Dubois
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Katelyn A
authors.initials: KA
authors.lastname: Medeiros
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Sat Dev
authors.initials: SD
authors.lastname: Batish
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jones
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Khalida
authors.initials: K
authors.lastname: Liaquat
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Hoffman
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Jaremko
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Quest Diagnostics, Nichols Institute, San Juan Capistrano, California.
authors.forename: Weimin
authors.initials: W
authors.lastname: Sun
authors.affiliation: Quest Diagnostics, Nichols Institute, San Juan Capistrano, California.
authors.forename: Arlene
authors.initials: A
authors.lastname: Buller-Burckle
authors.affiliation: Quest Diagnostics, Nichols Institute, San Juan Capistrano, California.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Strom
authors.affiliation: Quest Diagnostics, Nichols Institute, San Juan Capistrano, California.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Keiles
authors.affiliation: Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Higgins
mesh_terms: D019295:Computational Biology / Q000379:methods*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D023281:Genomics / Q000379:methods*; D006801:Humans; D015588:Observer Variation; D015203:Reproducibility of Results; D012984:Software; D064878:Web Browser
keywords: clinical laboratory techniques; databases; decision support techniques; mutation; nucleic acid; polymorphism