title: Panel Testing for Familial Breast Cancer: Calibrating the Tension Between Research and Clinical Care.
abstract: Gene panel sequencing is revolutionizing germline risk assessment for hereditary breast cancer. Despite scant evidence supporting the role of many of these genes in breast cancer predisposition, results are often reported to families as the definitive explanation for their family history. We assessed the frequency of mutations in 18 genes included in hereditary breast cancer panels among index cases from families with breast cancer and matched population controls.
  
  
  
  Cases (n = 2,000) were predominantly breast cancer-affected women referred to specialized Familial Cancer Centers on the basis of a strong family history of breast cancer and BRCA1 and BRCA2 wild type. Controls (n = 1,997) were cancer-free women from the LifePool study. Sequencing data were filtered for known pathogenic or novel loss-of-function mutations.
  
  
  
  Excluding 19 mutations identified in BRCA1 and BRCA2 among the cases and controls, a total of 78 cases (3.9%) and 33 controls (1.6%) were found to carry potentially actionable mutations. A significant excess of mutations was only observed for PALB2 (26 cases, four controls) and TP53 (five cases, zero controls), whereas no mutations were identified in STK11. Among the remaining genes, loss-of-function mutations were rare, with similar frequency between cases and controls.
  
  
  
  The frequency of mutations in most breast cancer panel genes among individuals selected for possible hereditary breast cancer is low and, in many cases, similar or even lower than that observed among cancer-free population controls. Although multigene panels can significantly aid in cancer risk management and expedite clinical translation of new genes, they equally have the potential to provide clinical misinformation and harm at the individual level if the data are not interpreted cautiously.
authors.affiliation: Ella R. Thompson, Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, Peter MacCallum Cancer Centre, East Melbourne; Ella R. Thompson, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, University of Melbourne, Melbourne, Victoria; Michelle W. Wong-Brown and Rodney J. Scott, The University of Newcastle and Hunter Medical Research Institute; Rodney J. Scott, Hunter Area Pathology Service, Newcastle, New South Wales, Australia; Na Li, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Gillian Mitchell, BC Cancer Agency, Vancouver, Canada.
authors.forename: Ella R
authors.initials: ER
authors.lastname: Thompson
authors.affiliation: Ella R. Thompson, Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, Peter MacCallum Cancer Centre, East Melbourne; Ella R. Thompson, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, University of Melbourne, Melbourne, Victoria; Michelle W. Wong-Brown and Rodney J. Scott, The University of Newcastle and Hunter Medical Research Institute; Rodney J. Scott, Hunter Area Pathology Service, Newcastle, New South Wales, Australia; Na Li, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Gillian Mitchell, BC Cancer Agency, Vancouver, Canada.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Rowley
authors.affiliation: Ella R. Thompson, Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, Peter MacCallum Cancer Centre, East Melbourne; Ella R. Thompson, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, University of Melbourne, Melbourne, Victoria; Michelle W. Wong-Brown and Rodney J. Scott, The University of Newcastle and Hunter Medical Research Institute; Rodney J. Scott, Hunter Area Pathology Service, Newcastle, New South Wales, Australia; Na Li, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Gillian Mitchell, BC Cancer Agency, Vancouver, Canada.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Ella R. Thompson, Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, Peter MacCallum Cancer Centre, East Melbourne; Ella R. Thompson, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, University of Melbourne, Melbourne, Victoria; Michelle W. Wong-Brown and Rodney J. Scott, The University of Newcastle and Hunter Medical Research Institute; Rodney J. Scott, Hunter Area Pathology Service, Newcastle, New South Wales, Australia; Na Li, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Gillian Mitchell, BC Cancer Agency, Vancouver, Canada.
authors.forename: Simone
authors.initials: S
authors.lastname: McInerny
authors.affiliation: Ella R. Thompson, Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, Peter MacCallum Cancer Centre, East Melbourne; Ella R. Thompson, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, University of Melbourne, Melbourne, Victoria; Michelle W. Wong-Brown and Rodney J. Scott, The University of Newcastle and Hunter Medical Research Institute; Rodney J. Scott, Hunter Area Pathology Service, Newcastle, New South Wales, Australia; Na Li, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Gillian Mitchell, BC Cancer Agency, Vancouver, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Devereux
authors.affiliation: Ella R. Thompson, Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, Peter MacCallum Cancer Centre, East Melbourne; Ella R. Thompson, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, University of Melbourne, Melbourne, Victoria; Michelle W. Wong-Brown and Rodney J. Scott, The University of Newcastle and Hunter Medical Research Institute; Rodney J. Scott, Hunter Area Pathology Service, Newcastle, New South Wales, Australia; Na Li, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Gillian Mitchell, BC Cancer Agency, Vancouver, Canada.
authors.forename: Michelle W
authors.initials: MW
authors.lastname: Wong-Brown
authors.affiliation: Ella R. Thompson, Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, Peter MacCallum Cancer Centre, East Melbourne; Ella R. Thompson, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, University of Melbourne, Melbourne, Victoria; Michelle W. Wong-Brown and Rodney J. Scott, The University of Newcastle and Hunter Medical Research Institute; Rodney J. Scott, Hunter Area Pathology Service, Newcastle, New South Wales, Australia; Na Li, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Gillian Mitchell, BC Cancer Agency, Vancouver, Canada.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Trainer
authors.affiliation: Ella R. Thompson, Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, Peter MacCallum Cancer Centre, East Melbourne; Ella R. Thompson, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, University of Melbourne, Melbourne, Victoria; Michelle W. Wong-Brown and Rodney J. Scott, The University of Newcastle and Hunter Medical Research Institute; Rodney J. Scott, Hunter Area Pathology Service, Newcastle, New South Wales, Australia; Na Li, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Gillian Mitchell, BC Cancer Agency, Vancouver, Canada.
authors.forename: Gillian
authors.initials: G
authors.lastname: Mitchell
authors.affiliation: Ella R. Thompson, Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, Peter MacCallum Cancer Centre, East Melbourne; Ella R. Thompson, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, University of Melbourne, Melbourne, Victoria; Michelle W. Wong-Brown and Rodney J. Scott, The University of Newcastle and Hunter Medical Research Institute; Rodney J. Scott, Hunter Area Pathology Service, Newcastle, New South Wales, Australia; Na Li, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Gillian Mitchell, BC Cancer Agency, Vancouver, Canada.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
authors.affiliation: Ella R. Thompson, Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, Peter MacCallum Cancer Centre, East Melbourne; Ella R. Thompson, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, University of Melbourne, Melbourne, Victoria; Michelle W. Wong-Brown and Rodney J. Scott, The University of Newcastle and Hunter Medical Research Institute; Rodney J. Scott, Hunter Area Pathology Service, Newcastle, New South Wales, Australia; Na Li, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Gillian Mitchell, BC Cancer Agency, Vancouver, Canada.
authors.forename: Paul A
authors.initials: PA
authors.lastname: James
authors.affiliation: Ella R. Thompson, Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, Peter MacCallum Cancer Centre, East Melbourne; Ella R. Thompson, Alison H. Trainer, Gillian Mitchell, Paul A. James, and Ian G. Campbell, University of Melbourne, Melbourne, Victoria; Michelle W. Wong-Brown and Rodney J. Scott, The University of Newcastle and Hunter Medical Research Institute; Rodney J. Scott, Hunter Area Pathology Service, Newcastle, New South Wales, Australia; Na Li, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Gillian Mitchell, BC Cancer Agency, Vancouver, Canada. ian.campbell@petermac.org.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Campbell
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins