Variant classification changes over time in BRCA1 and BRCA2
Variant classification changes over time in BRCA1 and BRCA2
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DOI：
10.1038/s41436-019-0493-2
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发表时间：
2019-10-01
影响因子：
8.8
通讯作者：
Lerner-Ellis, Jordan
中科院分区：
文献类型：
--
作者：
Mighton, Chloe;Charames, George S.;Lerner-Ellis, Jordan
目的：报告加拿大多伦多高级分子诊断实验室（AMDL）2012年至2017年期间对BRCA 1和BRCA 2（BRCA 1/2）变异的重新评估和重新分类，该实验室为安大略的患者提供BRCA 1/2检测，并将AMDL变异分类与ClinVar中的提交资料进行比较。方法：使用基于美国医学遗传学和基因组学学院/分子病理学协会指南的标准化变体评估工具评估变体，并在内部数据库中跟踪。变异体通过加拿大开放遗传学知识库共享，并提交给ClinVar与其他实验室进行比较。结果：AMDL在2012年至2017年期间鉴定了1209个BRCA 1/2变异体。在此期间，重新评估了32.9%（398/1209）的变异，重新分类了12.4%（150/1209）。大多数重新分类的变体被降级（112/150，74.7%）。在重新分类的变异中，63.3%（95/150）被重新分类为良性，20.7%（31/150）被重新分类为可能良性，10.0%（15/150）被重新分类为不确定意义的变异，2.0%（3/150）被重新分类为可能致病，4.0%（6/150）被重新分类为致病。40.4%（488/1209）的变异体被发现存在不一致的ClinVar提交。结论：BRCA 1/2变异体可能随着时间的推移而重新分类。重新分类提出了与重新接触患者相关的伦理和实践挑战。数据共享对于改善变异解释，帮助患者根据其遗传结果接受适当的护理至关重要。
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.