title: Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm.
abstract: Lynch syndrome is a hereditary cancer syndrome associated with high risks of colorectal and endometrial cancer that is caused by pathogenic variants in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM). Accurate classification of variants identified in these genes as pathogenic or benign enables informed medical management decisions. Previously, we developed a clinical History Weighting Algorithm (HWA) for the classification of variants of uncertain significance (VUSs) in BRCA1 and BRCA2. The BRCA1/2 HWA is based on the premise that pathogenic variants in these genes will be identified more often in individuals with strong personal and/or family histories of breast and/or ovarian cancer, while the identification of benign variants should be independent of cancer history. Here we report the development of a similar HWA to allow for classification of VUSs in genes associated with Lynch syndrome using data collected through both syndrome-specific and pan-cancer panel testing.
  
  
  
  Upon completion of algorithm development, the HWA was tested using simulated variants constructed from 79,214 probands, as well as 379 true variants. Positive (PPV) and negative predictive values (NPV) were calculated on a per gene basis.
  
  
  
  25,500 pathogenic and 50,500 benign simulated variants were analyzed using the HWA and the PPVs and NPVs for each gene were greater than 0.997 and 0.999, respectively. The HWA was also evaluated using 100 trials for each of the 379 true variants. PPVs of >0.998 and NPVs of >0.999 were obtained for all genes.
  
  
  
  We have developed and implemented a HWA to aid in the classification of VUSs in genes associated with Lynch syndrome. The work presented here demonstrates that this HWA is able to classify MLH1, MSH2, and MSH6 VUSs as either benign or pathogenic with high accuracy.
authors.affiliation: Myriad Genetics, Inc, 320 Wakara Way, Salt Lake City, UT, 84108, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Morris
authors.affiliation: Myriad Genetics, Inc, 320 Wakara Way, Salt Lake City, UT, 84108, USA.
authors.forename: Elisha
authors.initials: E
authors.lastname: Hughes
authors.affiliation: Myriad Genetic Laboratories, Inc, 320 Wakara Way, Salt Lake City, UT, 84108, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Rosenthal
authors.affiliation: Myriad Genetics, Inc, 320 Wakara Way, Salt Lake City, UT, 84108, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gutin
authors.affiliation: Myriad Genetic Laboratories, Inc, 320 Wakara Way, Salt Lake City, UT, 84108, USA. kbowles@myriad.com.
authors.forename: Karla R
authors.initials: KR
authors.lastname: Bowles
mesh_terms: D000465:Algorithms; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000145:classification* / Q000235:genetics; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein
keywords: Lynch syndrome; MLH1; MSH2; MSH6; Variant classification