title: Inactivation of DNA mismatch repair by variants of uncertain significance in the PMS2 gene.
abstract: Lynch syndrome (LS) is a common cancer predisposition caused by an inactivating mutation in one of four DNA mismatch repair (MMR) genes. Frequently a variant of uncertain significance (VUS), rather than an obviously pathogenic mutation, is identified in one of these genes. The inability to define pathogenicity of such variants precludes targeted healthcare. Here, we have modified a cell-free assay to test VUS in the MMR gene PMS2 for functional activity. We have analyzed nearly all VUS in PMS2 found thus far and describe loss of MMR activity for five, suggesting the applicability of the assay for diagnosis of LS.
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Drost
authors.forename: Hester
authors.initials: H
authors.lastname: Koppejan
authors.forename: Niels
authors.initials: N
authors.lastname: de Wind
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2
chemical_list: D004268:DNA-Binding Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes
keywords: DNA mismatch repair; Lynch syndrome; PMS2; VUS
references.citation: Hum Mutat. 2010 May;31(5):552-60
references.pmid: 20186689
references.citation: Hum Mutat. 2008 Nov;29(11):1265-72
references.pmid: 18951437
references.citation: Hum Mutat. 2013 Jan;34(1):255-65
references.pmid: 22949387
references.citation: Hum Mutat. 2006 May;27(5):490-5
references.pmid: 16619239
references.citation: J Med Genet. 2013 Aug;50(8):552-63
references.pmid: 23709753
references.citation: Nat Rev Clin Oncol. 2010 Apr;7(4):197-208
references.pmid: 20177404
references.citation: Lancet. 2011 Dec 17;378(9809):2081-7
references.pmid: 22036019
references.citation: Nat Rev Cancer. 2004 Oct;4(10):769-80
references.pmid: 15510158
references.citation: Genet Med. 2011 Feb;13(2):115-24
references.pmid: 21239990
references.citation: Gastroenterology. 2006 Feb;130(2):312-22
references.pmid: 16472587
references.citation: Hum Mutat. 2010 Mar;31(3):247-53
references.pmid: 20020535
references.citation: Cancer Res. 2004 Jul 15;64(14):4721-7
references.pmid: 15256438
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13384-9
references.pmid: 20624957
references.citation: Hum Mutat. 2012 Dec;33(12):1617-25
references.pmid: 22833534
references.citation: Cancer Lett. 2007 May 8;249(2):148-56
references.pmid: 17029773
references.citation: Gynecol Oncol. 1999 Sep;74(3):395-9
references.pmid: 10479499
references.citation: Int J Colorectal Dis. 2009 Aug;24(8):885-93
references.pmid: 19479271
references.citation: Proc Natl Acad Sci U S A. 1990 Aug;87(15):5837-41
references.pmid: 2116007
references.citation: Gastroenterology. 2008 Aug;135(2):419-28
references.pmid: 18602922
references.citation: Hum Genet. 1999 Jul-Aug;105(1-2):79-85
references.pmid: 10480359
references.citation: Hum Mutat. 2012 Mar;33(3):488-94
references.pmid: 22102614