Update of the UMD-VHL database: classification of 164 challenging variants based on genotype–phenotype correlation among 605 entries

Abstract

BackgroundThe von Hippel-Lindau (VHL) disease is a hereditary tumour syndrome caused by germline mutations inVHLtumour suppressor gene. The identification ofVHLvariants requires accurate classification which has an impact on patient management and genetic counselling.MethodsThe TENGEN (French oncogenetics network of neuroendocrine tumors) and PREDIR (French National Cancer Institute network for Inherited predispositions to kidney cancer) networks have collectedVHLgenetic variants and clinical characteristics of all VHL-suspected patients analysed from 2003 to 2021 by one of the nine laboratories performingVHLgenetic testing in France. Identified variants were registered in a locus-specific database, the Universal Mutation Database-VHL database (http://www.umd.be/VHL/).ResultsHere we report the expert classification of 164 variants, including all missense variants (n=124), all difficult interpretation variants (n=40) and their associated phenotypes. After initial American College of Medical Genetics classification, first-round classification was performed by the VHL expert group followed by a second round for discordant and ambiguous cases. Overall, the VHL experts modified the classification of 87 variants including 30 variants of uncertain significance that were as (likely)pathogenic variants for 19, and as likely benign for 11.ConclusionConsequently, this work has allowed the diagnosis and influenced the genetic counselling of 45 VHL-suspected families and can benefit to the worldwide VHL community, through this review.