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Locus-specific databases (LSDBs) which accept submissions of variants and their interpretation from diagnostic and research laboratories are subject to problems of duplicate entries, limited annotation of relevant clinical and experimental data, and variable quality of in silico analyses. In addition, ad hoc or generic criteria for interpretation lack refinement for gene specific interpretation, and do not draw on the specific expertise of clinicians and scientists directly working in the field relevant to the genes in question. As a result, interpretation of the same variant submitted from different sources can be discordant, leaving the database and the clinical field open to uncertainty, detracting from its utility for clinical application.
The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) has fostered the integration of all major mismatch repair databases into a single LSDB. InSiGHT has developed a coordinated approach to the authoritative interpretation of mismatch repair gene variants, engaging a range of gene specific experts, and drawing on comprehensive clinical and experimental information sourced from the published literature and from its own members. The InSiGHT Variant Interpretation Committee comprised of 40 experts in the mismatch repair field was tasked with variant review and classification on a pro bono basis. InSiGHT developed governance and support through incorporation, to protect the committee from possible legal challenge related to clinical use of its conclusions.
The Committee applied a standardized classification scheme to constitutional variants in the Lynch Syndrome genes MLH1, MSH2, MSH6 and PMS2, reviewing all clinical and functional data available for the variants . All 2,360 unique sequence alterations were considered and classified. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinically important misclassifications were identified for unique variants initially submitted as not pathogenic (54 unique variants reclassified as pathogenic and 25 reclassified as likely pathogenic) and unique variants submitted as pathogenic (28 unique variants reclassified as not pathogenic, 16 reclassified as likely not pathogenic and 218 reclassified as uncertain clinical significance). Importantly, the consensus results have been disseminated online through the InSiGHT database and ClinVar.
Consistent clinical management based on transparent evaluation is now possible for the 1,370 variants that are not obviously protein truncating (e.g. missense, single amino acid indels) based on their nomenclature. This large-scale endeavour demonstrates the value of multidisciplinary collaboration for curation and classification of variants in public locus-specific databases.