Journal article

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

Mark Drost, Yvonne Tiersma, Bryony A Thompson, Jane H Frederiksen, Guido Keijzers, Dylan Glubb, Scott Kathe, Jan Osinga, Helga Westers, Lisa Pappas, Kenneth M Boucher, Siska Molenkamp, Jose B Zonneveld, Christi J van Asperen, David E Goldgar, Susan S Wallace, Rolf H Sijmons, Amanda B Spurdle, Lene J Rasmussen, Marc S Greenblatt Show all

GENETICS IN MEDICINE | NATURE PUBLISHING GROUP | Published : 2019

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 assess..

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University of Melbourne Researchers

Grants

Awarded by US National Institutes of Health (NIH) National Cancer Institute (NCI)


Awarded by Australian National Health and Medical Research Council (NHMRC) Senior Research Fellowship


Awarded by NHMRC grant


Awarded by Harboefonden


Awarded by US NIH NCI


Awarded by Dutch Digestive Foundation


Awarded by NATIONAL CANCER INSTITUTE


Funding Acknowledgements

We appreciate the assistance of John-Paul Plazzer, curator of the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) Database. A.B.S., D.E.G., L.J.R., M.S.G., R.H.S., N.D.W., S.S.W., and S.V.T. are supported by US National Institutes of Health (NIH) National Cancer Institute (NCI) grant R01 CA164944. A.B.S. is supported by an Australian National Health and Medical Research Council (NHMRC) Senior Research Fellowship (ID1061779). B.A.T. is supported by an NHMRC CJ Martin Early Career Fellowship. D.G. was supported in part by an NHMRC grant (ID1109286) G.K. is supported by Harboefonden (grant number 15292), Familien Spogards Fond, and Fabrikant Einer Willumsens Mindelegat. K.M.B., L.P., and S.V.T. are supported by US NIH NCI grant P30 CA042014. L.J.R. is funded by Nordeafonden and the Olav Thon Foundation. N.D.W. is funded by the Dutch Digestive Foundation grant FP 16-012.