Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome

Heleen M. van der Klift*, Arjen R. Mensenkamp, Mark Drost, Elsa C. Bik, Yvonne J. Vos, Hans J. J. P. Gille, Bert E. J. W. Redeker, Yvonne Tiersma, Jose B. M. Zonneveld, Encarna Gomez Garcia, Tom G. W. Letteboer, Maran J. W. Olderode-Berends, Liselotte P. van Hest, Theo A. van Os, Senno Verhoef, Anja Wagner, Christi J. van Asperen, Sanne W. ten Broeke, Frederik J. Hes, Niels de WindMaartje Nielsen, Peter Devilee, Marjolijn J. L. Ligtenberg, Juul T. Wijnen, Carli M. J. Tops

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are applied to overcome problematic PMS2 mutation analysis due to the presence of pseudogenes and frequent gene conversion events. Here, we determined PMS2 mutation detection yield and mutation spectrum in a nationwide cohort of 396 probands. Furthermore, we studied concordance between tumor IHC/MSI (immunohistochemistry/microsatellite instability) profile and mutation carrier state. Overall, we found 52 different pathogenic PMS2 variants explaining 121 Lynch syndrome and nine CMMRD patients. In vitro mismatch repair assays suggested pathogenicity for three missense variants. Ninety-one PMS2 mutation carriers (70%) showed isolated loss of PMS2 in their tumors, for 31 (24%) no or inconclusive IHC was available, and eight carriers (6%) showed discordant IHC (presence of PMS2 or loss of both MLH1 and PMS2). Ten cases with isolated PMS2 loss (10%; 10/97) harbored MLH1 mutations. We confirmed that recently improved mutation analysis provides a high yield of PMS2 mutations in patients with isolated loss of PMS2 expression. Application of universal tumor prescreening methods will however miss some PMS2 germline mutation carriers.
Original languageEnglish
Pages (from-to)1162-1179
JournalHuman Mutation
Volume37
Issue number11
DOIs
Publication statusPublished - Nov 2016

Keywords

  • PMS2
  • Lynch syndrome
  • CMMRD
  • pseudogenes
  • missense variants
  • immunohistochemistry
  • mismatch repair
  • MLH1

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