RT Journal Article SR Electronic T1 Using structural analysis in silico to assess the impact of missense variants in MEN1 JF bioRxiv FD Cold Spring Harbor Laboratory SP 661512 DO 10.1101/661512 A1 Richard C. Caswell A1 Martina M. Owens A1 Adam C. Gunning A1 Sian Ellard A1 Caroline F. Wright YR 2019 UL http://biorxiv.org/content/early/2019/07/10/661512.abstract AB Despite the rapid expansion in recent years of databases reporting either benign or pathogenic genetic variation, the interpretation of novel missense variants can remain challenging, particularly for clinical or genetic testing laboratories where functional analysis is often unfeasible. Previous studies have shown that thermodynamic analysis of protein structure in silico can discriminate between groups of benign and pathogenic missense variants. However, although structures exist for many human disease-associated proteins, such analysis remains largely unexploited in clinical laboratories. Here, we analysed the predicted effect of 338 known missense variants on the structure of Menin, the MEN1 gene product. Results provided strong discrimination between pathogenic and benign variants, with a threshold of >4 kcal/mol for the predicted change in stability providing a strong indicator of pathogenicity. Subsequent analysis of 7 novel missense variants identified during clinical testing of MEN1 patients showed that all 7 were predicted to destabilise Menin by >4 kcal/mol. We conclude that structural analysis provides a useful tool in understanding the impact of missense variants in MEN1, and that integration of proteomic with genomic data could potentially contribute to the classification of novel variants in this disease.