The Frequency of Discordant Variant Classification in the Human Gene Mutation Database: A Comparison of the American College of Medical Genetics and Genomics Guidelines and ClinVar.

OBJECTIVE: Discordant variant classifications among public databases is one of the well-documented limitations when interpreting the pathogenicity of variants. The aim of this study is to investigate the level of germline variant misannotation from the Human Gene Mutation Database (HGMD) and the annotation concordance between databases.
METHODS: We used a total of 188,106 classified variants (disease-causing mutations [n = 179,454] and polymorphisms [n = 8652]) in 6466 genes from the HGMD. All variants were reanalyzed based on the American College of Medical Genetics and Genomics (ACMG) guidelines and compared to ClinVar database variants.
RESULTS: When variants were classified based on the ACMG guidelines, misclassification was observed in 3.47% (2289/65,896) of variants. The overall concordance between HGMD and ClinVar was 97.62% (52,499/53,780) of variants studied.
CONCLUSION: Variants in databases must be used with caution when variant pathogenicity is interpreted. This study reveals the frequency of misannotation of the HGMD variants and annotation concordance between databases in depth. © American Society for Clinical Pathology 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.