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Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome
Author(s) -
Klift Heleen M.,
Mensenkamp Arjen R.,
Drost Mark,
Bik Elsa C.,
Vos Yvonne J.,
Gille Hans J.J.P.,
Redeker Bert E.J.W.,
Tiersma Yvonne,
Zonneveld José B.M.,
García Encarna Gómez,
Letteboer Tom G.W.,
OlderodeBerends Maran J.W.,
Hest Liselotte P.,
Os Theo A.,
Verhoef Senno,
Wagner Anja,
Asperen Christi J.,
ten Broeke Sanne W.,
Hes Frederik J.,
Wind Niels,
Nielsen Maartje,
Devilee Peter,
Ligtenberg Marjolijn J.L.,
Wijnen Juul T.,
Tops Carli M.J.
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23052
Subject(s) - pms2 , lynch syndrome , mlh1 , biology , genetics , germline mutation , microsatellite instability , msh2 , mutation , dna mismatch repair , cancer research , dna repair , microsatellite , gene , allele
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.