Verification of the Three Step Model in Assessing the Pathogenicity of Mismatch Repair Gene Variants

Minttu Kansikas (1) , Reetta Kariola (1) , Minna Nystrom (1)

1 Department of Biosciences

To evaluate whether DNA mismatch repair (MMR) gene variations predispose to Lynch syndrome (LS), a three step assessment model has been proposed. Where LS is suspected, STEP1 is dedicated to the identification of the causative MMR gene and the variation. In STEP2, the functional effect of the variation is assessed in an in vitro MMR and in silico assays. Where LS cannot be confirmed or ruled out, more specific biochemical assays are required in STEP3. Here we verified the proposed model and its ability to distinguish pathogenic MMR variations from variants of uncertain significance by utilizing clinical, laboratory and in silico data of 37 MLH1, 26 MSH2 and 11 MSH6 variations. The proposed model was shown to be appropriate and proceed logically in assessing the pathogenicity of MMR variations. In fact, for MMR deficient MLH1 and MSH2 variations STEP3 is not required. STEP3 is important in assessing MMR proficient variations showing discrepant in silico results after STEP2. MSH6 variations require appropriate selection in terms of ruling out MLH1 and MSH2 variations and MLH1 promoter hypermethylation. Overall, taking into consideration the susceptibility gene, the three step model can be utilized in an efficient manner to determine the pathogenicity of MMR gene variations.

Mots clés: Life Sciences

Minttu Kansikas, Reetta Kariola, Minna Nystrom. Verification of the Three Step Model in Assessing the Pathogenicity of Mismatch Repair Gene Variants. Human Mutation, 2010, 32 (1), pp.107. ⟨10.1002/humu.21409⟩. ⟨hal-00602305⟩