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abstract:
Assessment of the InSiGHT Interpretation Criteria for the Clinical Classification of 24 MLH1 and MSH2 Gene Variants
15 SEP 2016
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.
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