Locus-Specific Databases (LSDBs) and Recommendations to StrengthenTheir Contribution to the Classification of Variants in Cancer SusceptibilityGenes

摘要

Locus Specific Databases (LSDBs) are curated collections of sequence variants in genes associated with disease. LSDBs of cancer-related genes often serve as a critical resource to researchers, diagnostic laboratories, clinicians, and others in the cancer genetics community. LSDBs are poised to play an important role in disseminating clinical classification of variants. The IARC Working Group on Unclassified Genetic Variants has proposed a new system of five classes of variants in cancer susceptibility genes. However, standards are lacking for reporting and analyzing the multiple data types that assist in classifying variants. By adhering to standards of transparency and consistency in the curation and annotation of data, LSDBs can be critical for organizing our understanding of how genetic variation relates to disease. This article discusses how LSDBs can accomplish these goals, using existing databases for BRCA1, BRCA2, MSH2, MLH1, TP53, and CDKN2A to illustrate the progress and remaining challenges in this field. We recommend that: 1) LSDBs should only report a conclusion related to pathogenicity if a consensus has been reached by an expert panel; 2) The system used to classify variants should be standardized. The Working Groupencourages use of the five class system described in ; 3) Evidence that supports aconclusion should be reported in the database, including sources and criteriaused for assignment; 4) Variants should only be classified as pathogenic if morethan one type of evidence has been considered, and 5) All instances of allvariants should be recorded.