Chloe Mighton1,2, George S Charames3,4,5, Marina Wang4, Kathleen-Rose Zakoor4,5, Andrew Wong4, Salma Shickh1,2, Nicholas Watkins4, Matthew S Lebo6,7, Yvonne Bombard1,2, Jordan Lerner-Ellis8,9,10. 1. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada. 2. Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada. 3. Department of Pathology and Laboratory Medicine, University of Toronto, Toronto, ON, Canada. 4. Mount Sinai Hospital, Laboratory Medicine and Pathobiology, Sinai Health System, University of Toronto, Toronto, ON, Canada. 5. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada. 6. Laboratory for Molecular Medicine Cambridge, Partners Healthcare for Personalized Medicine, Cambridge, MA, USA. 7. Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 8. Department of Pathology and Laboratory Medicine, University of Toronto, Toronto, ON, Canada. Jordan.Lerner-Ellis@sinaihealthsystem.ca. 9. Mount Sinai Hospital, Laboratory Medicine and Pathobiology, Sinai Health System, University of Toronto, Toronto, ON, Canada. Jordan.Lerner-Ellis@sinaihealthsystem.ca. 10. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada. Jordan.Lerner-Ellis@sinaihealthsystem.ca.
Abstract
PURPOSE: To report BRCA1 and BRCA2 (BRCA1/2) variant reassessments and reclassifications between 2012 and 2017 at the Advanced Molecular Diagnostics Laboratory (AMDL) in Toronto, Canada, which provides BRCA1/2 testing for patients in Ontario, and to compare AMDL variant classifications with submissions in ClinVar. METHODS: Variants were assessed using a standardized variant assessment tool based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology's guidelines and tracked in an in-house database. Variants were shared through the Canadian Open Genetics Repository and submitted to ClinVar for comparison against other laboratories. RESULTS: AMDL identified 1209 BRCA1/2 variants between 2012 and 2017. During this period, 32.9% (398/1209) of variants were reassessed and 12.4% (150/1209) were reclassified. The majority of reclassified variants were downgraded (112/150, 74.7%). Of the reclassified variants, 63.3% (95/150) were reclassified to benign, 20.7% (31/150) to likely benign, 10.0% (15/150) to variant of uncertain significance, 2.0% (3/150) to likely pathogenic, and 4.0% (6/150) to pathogenic. Discordant ClinVar submissions were found for 40.4% (488/1209) of variants. CONCLUSION: BRCA1/2 variants may be reclassified over time. Reclassification presents ethical and practical challenges related to recontacting patients. Data sharing is essential to improve variant interpretation, to help patients receive appropriate care based on their genetic results.
PURPOSE: To report BRCA1 and BRCA2 (BRCA1/2) variant reassessments and reclassifications between 2012 and 2017 at the Advanced Molecular Diagnostics Laboratory (AMDL) in Toronto, Canada, which provides BRCA1/2 testing for patients in Ontario, and to compare AMDL variant classifications with submissions in ClinVar. METHODS: Variants were assessed using a standardized variant assessment tool based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology's guidelines and tracked in an in-house database. Variants were shared through the Canadian Open Genetics Repository and submitted to ClinVar for comparison against other laboratories. RESULTS: AMDL identified 1209 BRCA1/2 variants between 2012 and 2017. During this period, 32.9% (398/1209) of variants were reassessed and 12.4% (150/1209) were reclassified. The majority of reclassified variants were downgraded (112/150, 74.7%). Of the reclassified variants, 63.3% (95/150) were reclassified to benign, 20.7% (31/150) to likely benign, 10.0% (15/150) to variant of uncertain significance, 2.0% (3/150) to likely pathogenic, and 4.0% (6/150) to pathogenic. Discordant ClinVar submissions were found for 40.4% (488/1209) of variants. CONCLUSION: BRCA1/2 variants may be reclassified over time. Reclassification presents ethical and practical challenges related to recontacting patients. Data sharing is essential to improve variant interpretation, to help patients receive appropriate care based on their genetic results.
Authors: Chloe Mighton; Amanda C Smith; Justin Mayers; Robert Tomaszewski; Sherryl Taylor; Stacey Hume; Ron Agatep; Elizabeth Spriggs; Harriet E Feilotter; Laura Semenuk; Henry Wong; Lorena Lazo de la Vega; Christian R Marshall; Michelle M Axford; Talia Silver; George S Charames; Vanessa Di Gioacchino; Nicholas Watkins; William D Foulkes; Marcos Clavier; Nancy Hamel; George Chong; Ryan E Lamont; Jillian Parboosingh; Aly Karsan; Ian Bosdet; Sean S Young; Tracy Tucker; Mohammad Reza Akbari; Marsha D Speevak; Andrea K Vaags; Matthew S Lebo; Jordan Lerner-Ellis Journal: J Med Genet Date: 2021-04-19 Impact factor: 5.941
Authors: Julia El Mecky; Lennart Johansson; Mirjam Plantinga; Angela Fenwick; Anneke Lucassen; Trijnie Dijkhuizen; Annemieke van der Hout; Kate Lyle; Irene van Langen Journal: BMC Med Genomics Date: 2019-11-29 Impact factor: 3.063
Authors: Jeroen van Rooij; Pascal Arp; Linda Broer; Joost Verlouw; Frank van Rooij; Robert Kraaij; André Uitterlinden; Annemieke J M H Verkerk Journal: Genet Med Date: 2020-07-15 Impact factor: 8.822