Assessment of the InSiGHT Interpretation Criteria for the Clinical Classification of 24 MLH1 and MSH2 Gene Variants

Rossella Tricarico, Mariann Kasela, Cristina Mareni, Bryony A Thompson, Aurélie Drouet, Lucia Staderini, Greta Gorelli, Francesca Crucianelli, Valentina Ingrosso, Jukka Kantelinen, Laura Papi, Maria De Angioletti, Margherita Berardi, Pascaline Gaildrat, Omar Soukarieh, Daniela Turchetti, Alexandra Martins, Amanda B Spurdle, Minna Nyström, Maurizio GenuardiInSiGHT Variant Intepretation Committee, Susan Farrington (Member of Group Organisation)

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Pathogenicity assessment of DNA variants in disease genes to explain their clinical consequences is an integral component of diagnostic molecular testing. The International Society for Gastrointestinal Hereditary Tumors (InSiGHT) has developed specific criteria for the interpretation of mismatch repair (MMR) gene variants. Here, we performed a systematic investigation of 24 MLH1 and MSH2 variants. The assessments were done by analyzing population frequency, segregation, tumor molecular characteristics, RNA effects, protein expression levels and in vitro MMR activity. Classifications were confirmed for 15 variants and changed for 3, and for the first time determined for 6 novel variants. Overall, based on our results we propose the introduction of some refinements to the InSiGHT classification rules. The proposed changes have the advantage of homogenizing the InSIGHT interpretation criteria with those set out by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium for the BRCA1/BRCA2 genes. We also observed that the addition of only few clinical data was sufficient to obtain a more stable classification for variants considered as "likely pathogenic" or "likely non pathogenic". This shows the importance of obtaining as many as possible points of evidence for variant interpretation, especially from the clinical setting. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalHuman Mutation: Variation, Informatics and Disease
Issue number1
Early online date15 Sept 2016
Publication statusPublished - Jan 2017


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