Chloe Mighton1,2,3, Conxi Lazaro1,4,5, Jordan Lerner-Ellis6,7,8, Nicholas Watkins1,9, Vanessa Di Gioacchino1, Andrew Wong1, Martin C Chang10,11, George S Charames10,1,12. 1. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, ON, Canada. 2. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada. 3. Genomics Health Services Research Program, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada. 4. Hereditary Cancer Program, ICO-IDIBELL, Barcelona, Spain. 5. Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada. 6. Department of Laboratory Medicine and Pathobiology, University of Toronto, 600 University Avenue, Toronto, ON, M5G 1X5, Canada. Jordan.Lerner-Ellis@SinaiHealth.ca. 7. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, ON, Canada. Jordan.Lerner-Ellis@SinaiHealth.ca. 8. Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada. Jordan.Lerner-Ellis@SinaiHealth.ca. 9. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. 10. Department of Laboratory Medicine and Pathobiology, University of Toronto, 600 University Avenue, Toronto, ON, M5G 1X5, Canada. 11. University of Vermont Cancer Center, Burlington, VT, USA. 12. Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada.
Abstract
PURPOSE: The aim of this study was to determine the diagnostic yield of multigene panel testing among patients referred with hereditary breast and ovarian cancer (HBOC). METHODS: Patients who met provincial eligibility criteria were tested at the Advanced Molecular Diagnostic Laboratory at Mount Sinai Hospital, Toronto. Gene sequencing and exon-level copy number variant (CNV) analysis was performed. The referring physician had the opportunity to choose between several different gene panels based on patient phenotype. Cases were included in the analysis based on personal and family history of cancer and the type of panel ordered. RESULTS: 3251 cases that received panel testing were included in this analysis. Overall, 9.1% (295) had a positive (pathogenic or likely pathogenic) result and 27.1% (882) had an inconclusive result (variant of uncertain significance). The genes with the highest prevalence of positive results were in BRCA2 (2.2%, 71/3235), BRCA1 (1.9%, 62/3235), and CHEK2 (1.4%, 40/2916). Of the positive cases, 9.8% (29) had a pathogenic or likely pathogenic variant in a gene associated with Lynch syndrome (MSH6, MSH2, MLH1, or PMS2). CONCLUSIONS: Our overall positive yield is similar to that reported in the literature. The yield of inconclusive results was three times that of positive results. By testing more individuals in families with HBOC and through data-sharing efforts, the clinical significance of most variants may eventually be determined and panel testing for monogenic cancer predisposition syndromes will have greater utility.
PURPOSE: The aim of this study was to determine the diagnostic yield of multigene panel testing among patients referred with hereditary breast and ovarian cancer (HBOC). METHODS:Patients who met provincial eligibility criteria were tested at the Advanced Molecular Diagnostic Laboratory at Mount Sinai Hospital, Toronto. Gene sequencing and exon-level copy number variant (CNV) analysis was performed. The referring physician had the opportunity to choose between several different gene panels based on patient phenotype. Cases were included in the analysis based on personal and family history of cancer and the type of panel ordered. RESULTS: 3251 cases that received panel testing were included in this analysis. Overall, 9.1% (295) had a positive (pathogenic or likely pathogenic) result and 27.1% (882) had an inconclusive result (variant of uncertain significance). The genes with the highest prevalence of positive results were in BRCA2 (2.2%, 71/3235), BRCA1 (1.9%, 62/3235), and CHEK2 (1.4%, 40/2916). Of the positive cases, 9.8% (29) had a pathogenic or likely pathogenic variant in a gene associated with Lynch syndrome (MSH6, MSH2, MLH1, or PMS2). CONCLUSIONS: Our overall positive yield is similar to that reported in the literature. The yield of inconclusive results was three times that of positive results. By testing more individuals in families with HBOC and through data-sharing efforts, the clinical significance of most variants may eventually be determined and panel testing for monogenic cancer predisposition syndromes will have greater utility.
Entities:
Keywords:
Breast cancer; Genetic testing; Multigene panel testing; Next-generation sequencing; Ovarian cancer
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