title: Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome.
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.
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands. hvdklift@lumc.nl.|Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands. hvdklift@lumc.nl.
authors.forename: Heleen M
authors.initials: HM
authors.lastname: van der Klift
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Arjen R
authors.initials: AR
authors.lastname: Mensenkamp
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Drost
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Elsa C
authors.initials: EC
authors.lastname: Bik
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Yvonne J
authors.initials: YJ
authors.lastname: Vos
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Hans J J P
authors.initials: HJ
authors.lastname: Gille
authors.affiliation: Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Bert E J W
authors.initials: BE
authors.lastname: Redeker
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Tiersma
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: José B M
authors.initials: JB
authors.lastname: Zonneveld
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Encarna Gómez
authors.initials: EG
authors.lastname: García
authors.affiliation: Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Tom G W
authors.initials: TG
authors.lastname: Letteboer
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Maran J W
authors.initials: MJ
authors.lastname: Olderode-Berends
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Liselotte P
authors.initials: LP
authors.lastname: van Hest
authors.affiliation: Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Theo A
authors.initials: TA
authors.lastname: van Os
authors.affiliation: Netherlands Cancer Institute, Amsterdam, The Netherlands.|Clinical Genetics Service, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Senno
authors.initials: S
authors.lastname: Verhoef
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Anja
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Christi J
authors.initials: CJ
authors.lastname: van Asperen
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Sanne W
authors.initials: SW
authors.lastname: Ten Broeke
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: de Wind
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: Nielsen
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.|Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Juul T
authors.initials: JT
authors.lastname: Wijnen
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Carli M J
authors.initials: CM
authors.lastname: Tops
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D053842:Microsatellite Instability; D000070976:Mismatch Repair Endonuclease PMS2 / Q000235:genetics* / Q000378:metabolism; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000378:metabolism; D009426:Netherlands
chemical_list: C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2
keywords: CMMRD; Lynch syndrome; MLH1; PMS2; immunohistochemistry; mismatch repair; missense variants; pseudogenes