Inactivation of DNA Mismatch Repair by Variants of Uncertain Significance in the PMS 2 Gene

Lynch syndrome ( LS ) is a common cancer predisposition caused by an inactivating mutation in one of four DNA mismatch repair ( MMR ) genes. Frequently a variant of uncertain significance ( VUS ), rather than an obviously pathogenic mutation, is identified in one of these genes. The inability to define pathogenicity of such variants precludes targeted healthcare. Here, we have modified a cell‐free assay to test VUS in the MMR gene PMS 2 for functional activity. We have analyzed nearly all VUS in PMS 2 found thus far and describe loss of MMR activity for five, suggesting the applicability of the assay for diagnosis of LS .