A functional assay-based procedure to classify mismatch repair gene variants in Lynch syndrome.

ABSTRACT:

Purpose

To enhance classification of variants of uncertain significance (VUS) in the DNA mismatch repair (MMR) genes in the cancer predisposition Lynch syndrome, we developed the cell-free in vitro MMR activity (CIMRA) assay. Here, we calibrate and validate the assay, enabling its integration with in silico and clinical data.

Methods

Two sets of previously classified MLH1 and MSH2 variants were selected from a curated MMR gene database, and their biochemical activity determined by the CIMRA assay. The assay was calibrated by regression analysis followed by symmetric cross-validation and Bayesian integration with in silico predictions of pathogenicity. CIMRA assay reproducibility was assessed in four laboratories.

Results

Concordance between the training runs met our p

SUBMITTER: Drost M 

PROVIDER: S-EPMC7901556 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature