title: Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes.
abstract: BRCA1 and BRCA2 sequencing analysis detects variants of uncertain clinical significance in approximately 2 % of patients undergoing clinical diagnostic testing in our laboratory. The reclassification of these variants into either a pathogenic or benign clinical interpretation is critical for improved patient management. We developed a statistical variant reclassification tool based on the premise that probands with disease-causing mutations are expected to have more severe personal and family histories than those having benign variants. The algorithm was validated using simulated variants based on approximately 145,000 probands, as well as 286 BRCA1 and 303 BRCA2 true variants. Positive and negative predictive values of ≥99 % were obtained for each gene. Although the history weighting algorithm was not designed to detect alleles of lower penetrance, analysis of the hypomorphic mutations c.5096G>A (p.Arg1699Gln; BRCA1) and c.7878G>C (p.Trp2626Cys; BRCA2) indicated that the history weighting algorithm is able to identify some lower penetrance alleles. The history weighting algorithm is a powerful tool that accurately assigns actionable clinical classifications to variants of uncertain clinical significance. While being developed for reclassification of BRCA1 and BRCA2 variants, the history weighting algorithm is expected to be applicable to other cancer- and non-cancer-related genes.
authors.affiliation: Myriad Genetics, Inc., Salt Lake City, UT, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Pruss
authors.forename: Brian
authors.initials: B
authors.lastname: Morris
authors.forename: Elisha
authors.initials: E
authors.lastname: Hughes
authors.forename: Julie M
authors.initials: JM
authors.lastname: Eggington
authors.forename: Lisa
authors.initials: L
authors.lastname: Esterling
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Robinson
authors.forename: Aric
authors.initials: A
authors.lastname: van Kan
authors.forename: Priscilla H
authors.initials: PH
authors.lastname: Fernandes
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Roa
authors.forename: Alexander
authors.initials: A
authors.lastname: Gutin
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wenstrup
authors.forename: Karla R
authors.initials: KR
authors.lastname: Bowles
mesh_terms: D000465:Algorithms; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000145:classification* / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D009367:Neoplasm Staging; D011379:Prognosis
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human