Sources of discordance among germ-line variant classifications in ClinVar

作者：Yang Shan; Lincoln Stephen E; Kobayashi Yuya; Nykamp Keith; Nus**aum Robert L; Topper Scott

来源：Genetics in Medicine, 2017, 19(10): 1118-1126.

DOI：10.1038/gim.2017.60

• clinical genetic testing
• ClinVar
• concordance
• data sharing
• variant interpretation

Purpose: ClinVar is increasingly used as a resource for both genetic variant interpretation and clinical practice. However, controversies exist regarding the consistency of classifications in ClinVar, and questions remain about how best to use these data. Our study systematically examined ClinVar to identify common sources of discordance and thus inform ongoing practices.
Methods: We analyzed variants that had multiple classifications in ClinVar, excluding benign polymorphisms. Classifications were categorized by potential actionability and pathogenicity. Consensus interpretations were calculated for each variant, and the properties of the discordant outlier classifications were summarized.
Results: Our study included 74,065 classifications of 27,224 unique variants in 1,713 genes. We found that (i) concordance rates differed among clinical areas and variant types; (ii) clinical testing methods had much higher concordance than basic literature curation and research efforts; (iii) older classifications had greater discordance than newer ones; and (iv) low-penetrance variants had particularly high discordance.
Conclusion: Recent variant classifications from clinical testing laboratories have high overall concordance in many (but not all) clinical areas. ClinVar can be a reliable resource supporting variant interpretation, quality assessment, and clinical practice when factors uncovered in this study are taken into account. Ongoing improvements to ClinVar may make it easier to use, particularly for nonexpert users.

• 出版日期2017-10