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Improving performance of multigene panels for genomic analysis of cancer predisposition.
Shirts, Brian H; Casadei, Silvia; Jacobson, Angela L; Lee, Ming K; Gulsuner, Suleyman; Bennett, Robin L; Miller, Margaret; Hall, Sarah A; Hampel, Heather; Hisama, Fuki M; Naylor, Lorraine V; Goetsch, Cathleen; Leppig, Kathleen; Tait, Jonathan F; Scroggins, Sheena M; Turner, Emily H; Livingston, Robert; Salipante, Stephen J; King, Mary-Claire; Walsh, Tom; Pritchard, Colin C.
Affiliation
  • Shirts BH; Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
  • Casadei S; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Jacobson AL; Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
  • Lee MK; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Gulsuner S; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Bennett RL; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Miller M; Providence Alaska Medical Center, Anchorage, Alaska, USA.
  • Hall SA; Kadlec Regional Medical Center, Richland, Washington, USA.
  • Hampel H; Division of Human Genetics, Department of Internal Medicine, Ohio State University, Columbus, Ohio, USA.
  • Hisama FM; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Naylor LV; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Goetsch C; Cancer Institute, Virginia Mason, Seattle, Washington, USA.
  • Leppig K; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Tait JF; Clinical Genetics, Group Health Cooperative, Seattle, Washington, USA.
  • Scroggins SM; Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
  • Turner EH; Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
  • Livingston R; Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
  • Salipante SJ; Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
  • King MC; Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
  • Walsh T; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Pritchard CC; Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Genet Med ; 18(10): 974-81, 2016 10.
Article in En | MEDLINE | ID: mdl-26845104
ABSTRACT

PURPOSE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Breast Neoplasms / Colorectal Neoplasms / Genetic Predisposition to Disease / Neoplasm Proteins Type of study: Etiology_studies / Guideline / Prognostic_studies / Risk_factors_studies Limits: Adult / Female / Humans / Middle aged Language: En Journal: Genet Med Journal subject: GENETICA MEDICA Year: 2016 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Breast Neoplasms / Colorectal Neoplasms / Genetic Predisposition to Disease / Neoplasm Proteins Type of study: Etiology_studies / Guideline / Prognostic_studies / Risk_factors_studies Limits: Adult / Female / Humans / Middle aged Language: En Journal: Genet Med Journal subject: GENETICA MEDICA Year: 2016 Type: Article Affiliation country: United States