title: Assessment of incidental findings in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics.
abstract: OBJECTIVE
  In March 2013 the American College of Medical Genetics and Genomics published a list of 56 genes with the recommendation that pathogenic and likely pathogenic variants detected incidentally by clinical sequencing be reported to patients. As an initial step in determining the practical consequences of this recommendation in the research setting, we searched for variants in these genes in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics.
  
  
  METHODS
  We identified rare, nonsynonymous, and splicing single-nucleotide variants and insertions/deletions and assessed variant classification using the Human Gene Mutation, Emory, and ClinVar databases. We analyzed the burden of mutation in each of the 56 genes and determined which variants should be reported to patients.
  
  
  RESULTS
  Our filtering resulted in 249 distinct variants, with a mean of 1.69 variants per individual. Half of these were novel missense mutations not classified by any of the three reference databases. Of 101 variants listed in the Human Gene Mutation Database, 48 were also in ClinVar and 3 were also in Emory; half of these shared variants were classified discordantly between databases. Some genes consistently had greater variation than others. In total, 0.86% of individuals had a reportable incidental variant.
  
  
  CONCLUSIONS
  These observations demonstrate some current challenges of assessing phenotypic consequences of incidental variants for counseling patients.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Julie
authors.identifier: http://orcid.org/0000-0003-4822-9384
authors.initials: J
authors.lastname: Jurgens
authors.affiliation: Center for Inherited Disease Research, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Ling
authors.affiliation: Center for Inherited Disease Research, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Hetrick
authors.affiliation: Center for Inherited Disease Research, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pugh
authors.affiliation: FS Consulting, Salem, Massachusetts, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Schiettecatte
authors.affiliation: Center for Inherited Disease Research, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kimberly
authors.identifier: http://orcid.org/0000-0001-8806-5738
authors.initials: K
authors.lastname: Doheny
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ada
authors.initials: A
authors.lastname: Hamosh
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Avramopoulos
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: David
authors.initials: D
authors.lastname: Valle
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Nara
authors.initials: N
authors.lastname: Sobreira
mesh_terms: D030561:Databases, Nucleic Acid; D059472:Exome; D005260:Female; D030342:Genetic Diseases, Inborn / Q000175:diagnosis / Q000235:genetics; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D033162:Incidental Findings; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide