title: Improving performance of multigene panels for genomic analysis of cancer predisposition.
abstract: Screening multiple genes for inherited cancer predisposition expands opportunities for cancer prevention; however, reports of variants of uncertain significance (VUS) may limit clinical usefulness. We used an expert-driven approach, exploiting all available information, to evaluate multigene panels for inherited cancer predisposition in a clinical series that included multiple cancer types and complex family histories.
  
  
  
  For 1,462 sequential patients referred for testing by BROCA or ColoSeq multigene panels, genomic DNA was sequenced and variants were interpreted by multiple experts using International Agency for Research on Cancer guidelines and incorporating evolutionary conservation, known and predicted variant consequences, and personal and family cancer history. Diagnostic yield was evaluated for various presenting conditions and family-history profiles.
  
  
  
  Of 1,462 patients, 12% carried damaging mutations in established cancer genes. Diagnostic yield varied by clinical presentation. Actionable results were identified for 13% of breast and colorectal cancer patients and for 4% of cancer-free subjects, based on their family histories of cancer. Incidental findings explaining cancer in neither the patient nor the family were present in 1.7% of subjects. Less than 1% of patients carried VUS in BRCA1 or BRCA2. For all genes combined, initial reports contained VUS for 10.5% of patients, which declined to 7.5% of patients after reclassification based on additional information.
  
  
  
  Individualized interpretation of gene panels is a complex medical activity. Interpretation by multiple experts in the context of personal and family histories maximizes actionable results and minimizes reports of VUS.Genet Med 18 10, 974-981.
authors: Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
authors: Brian H
authors: BH
authors: Shirts
authors: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors: Silvia
authors: S
authors: Casadei
authors: Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
authors: Angela L
authors: AL
authors: Jacobson
authors: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors: Ming K
authors: MK
authors: Lee
authors: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors: Suleyman
authors: S
authors: Gulsuner
authors: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors: Robin L
authors: RL
authors: Bennett
authors: Providence Alaska Medical Center, Anchorage, Alaska, USA.
authors: Margaret
authors: M
authors: Miller
authors: Kadlec Regional Medical Center, Richland, Washington, USA.
authors: Sarah A
authors: 0000-0002-9997-1223
authors: SA
authors: Hall
authors: Division of Human Genetics, Department of Internal Medicine, Ohio State University, Columbus, Ohio, USA.
authors: Heather
authors: 0000-0001-7558-9794
authors: H
authors: Hampel
authors: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors: Fuki M
authors: FM
authors: Hisama
authors: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors: Lorraine V
authors: LV
authors: Naylor
authors: Cancer Institute, Virginia Mason, Seattle, Washington, USA.
authors: Cathleen
authors: C
authors: Goetsch
authors: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.|Clinical Genetics, Group Health Cooperative, Seattle, Washington, USA.
authors: Kathleen
authors: K
authors: Leppig
authors: Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
authors: Jonathan F
authors: JF
authors: Tait
authors: Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
authors: Sheena M
authors: SM
authors: Scroggins
authors: Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
authors: Emily H
authors: 0000-0001-9040-9229
authors: EH
authors: Turner
authors: Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
authors: Robert
authors: 0000-0002-7424-2956
authors: R
authors: Livingston
authors: Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
authors: Stephen J
authors: SJ
authors: Salipante
authors: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.|Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors: Mary-Claire
authors: MC
authors: King
authors: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors: Tom
authors: T
authors: Walsh
authors: Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
authors: Colin C
authors: CC
authors: Pritchard
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D012307:Risk Factors
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D009363:Neoplasm Proteins