Determining the functional significance of mismatch repair gene missense variants using biochemical and cellular assays

Hereditary Cancer in Clinical Practice

Volumn 10, Issue 1, 2012, Pages

  Heinen, Christopher D ^a   Juel Rasmussen, Lene ^b  

^a UNIVERSITY OF CONNECTICUT HEALTH CENTER   (United States)

^b UNIVERSITY OF COPENHAGEN   (Denmark)

Author keywords

Hereditary nonpolyposis colorectal cancer; Lynch syndrome; Mismatch repair; MLH1; MSH2; MSH6; Variants of uncertain significance

Indexed keywords

FLUOROURACIL; METHYLNITROSOUREA;

ARTICLE; CELL ASSAY; COLORECTAL CANCER; DECISION MAKING; DNA DAMAGE; DNA REPLICATION; GENE LOCUS; GENETIC SCREENING; HEREDITARY NONPOLYPOSIS COLORECTAL CANCER; HUMAN; IN VITRO STUDY; MISMATCH REPAIR; MISSENSE MUTATION; NONHUMAN; NUCLEAR LOCALIZATION SIGNAL; PROTEIN FUNCTION; RNA SPLICING; YEAST;

EID: 84865734027     PISSN: 17312302     EISSN: 18974287     Source Type: Journal    
DOI: 10.1186/1897-4287-10-9     Document Type: Article

References (98)

1. Lynch H, Lynch P, Lanspa S, Snyder C, Lynch J, Boland C. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009, 76:1-18.
2. Peltomaki P. Lynch Syndrome Genes. Fam Cancer 2005, 4:227-232.
3. Nagasaka T, Rhees J, Kloor M, Gebert J, Naomoto Y, Boland CR, Goel A. Somatic Hypermethylation of MSH2 Is a Frequent Event in Lynch Syndrome Colorectal Cancers. Cancer Res 2010, 70:3098-3108.
4. Peltomaki P, Vasen H. Mutations associated with HNPCC predisposition - Update of ICG-HNPCC/INSiGHT mutation database. Dis Markers 2004, 20:269-276.
5. Peltomaki P, Vasen HF. Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 1997, 113:1146-1158.
6. Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Nakagawa H, Sotamaa K, Prior TW, Westman J, et al. Screening for the Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer). N Engl J Med 2005, 352:1851-1860.
7. Lindor NM, Burgart LJ, Leontovich O, Goldberg RM, Cunningham JM, Sargent DJ, Walsh-Vockley C, Petersen GM, Walsh MD, Leggett BA, et al. Immunohistochemistry Versus Microsatellite Instability Testing in Phenotyping Colorectal Tumors. J Clin Oncol 2002, 20:1043-1048.
8. Muller W, Burgart LJ, Krause-Paulus R, Thibodeau SN, Almeida M, Edmonston TB, Boland CR, Sutter C, Jass JR, Lindblom A, et al. The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC): Results of an international collaborative study. Fam Cancer 2001, V1:87-93.
9. Couch F, Rasmussen L, Hofstra R, Monteiro A, Greenblatt M, de Wind N, . for the IARC Unclassified Genetic Variants Working Group Assessment of functional effects of unclassified genetic variants. Hum Mutat 2008, 29:1314-1326. for the IARC Unclassified Genetic Variants Working Group.
10. Chao E, Velasquez J, Witherspoon M, Rozek L, Peel D, Ng P, Gruber S, Watson P, Rennert G, Anton-Culver H, et al. Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Hum Mutat 2008, 29:852-860.
11. Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol 2006, 7:335-346.
12. Kolodner RD, Marsischky GT. Eukaryotic DNA mismatch repair. Curr Opin Genet Dev 1999, 9:89-96.
13. Modrich P. Mechanisms in eukaryotic mismatch repair. J Biol Chem 2006, 281:30305-30309.
14. Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R. hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc Natl Acad Sci U S A 1996, 93:13629-13634.
15. Fishel R. Mismatch repair, molecular switches, and signal transduction. Genes Dev 1998, 12:2096-2101.
16. Kadyrov FA, Dzantiev L, Constantin N, Modrich P. Endonucleolytic Function of MutLa in Human Mismatch Repair. Cell 2006, 126:297-308.
17. Fishel R, Kolodner RD. Identification of mismatch repair genes and their role in the development of cancer. Curr Opin Genet Dev 1995, 5:382-395.
18. Duval A, Hamelin R. Mutations at Coding Repeat Sequences in Mismatch Repair-deficient Human Cancers: Toward a New Concept of Target Genes for Instability. Cancer Res 2002, 62:2447-2454.
19. Zhang Y, Yuan F, Presnell SR, Tian K, Gao Y, Tomkinson A, Gu L, Li G-M. Reconstitution of 5'-Directed Human Mismatch Repair in a Purified System. Cell 2005, 122:693-705.
20. Dzantiev L, Constantin N, Genschel J, Iyer RR, Burgers PM, Modrich P. A defined human system that supports bidirectional mismatch-provoked excision. Mol Cell 2004, 15:31-41.
21. Holmes J, Clark S, Modrich P. Strand-Specific Mismatch Correction in Nuclear Extracts of Human and Drosophila melanogaster Cell Lines. PNAS 1990, 87:5837-5841.
22. Heinen CD. Genotype to phenotype: Analyzing the effects of inherited mutations in colorectal cancer families. Mutat Res/DNA Repair 2010, 693:32-45.
23. Ou J, Niessen R, Lützen A, Sijmons R, Kleibeuker J, de Wind N, Rasmussen L, Hofstra R. Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. Hum Mutat 2007, 28:1047-1054.
24. Drost M, Zonneveld JBM, van Dijk L, Morreau H, Tops CM, Vasen HFA, Wijnen JT, de Wind N. A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1. Hum Mutat 2010, 31:247-253.
25. Drost M, Zonneveld JBM, van Hees S, Rasmussen LJ, Hofstra RMW, de Wind N. A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. Hum Mutat 2012, 33:488-494.
26. Guerrette S, Wilson T, Gradia S, Fishel R. Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer. Mol Cell Biol 1998, 18:6616-6623.
27. Guerrette S, Acharya S, Fishel R. The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. J Biol Chem 1999, 274:6336-6341.
28. Cyr JL, Heinen CD. Hereditary Cancer-associated Missense Mutations in hMSH6 Uncouple ATP Hydrolysis from DNA Mismatch Binding. J Biol Chem 2008, 283:31641-31648.
29. Heinen CD, Wilson T, Mazurek A, Berardini M, Butz C, Fishel R. HNPCC mutations in hMSH2 result in reduced hMSH2-hMSH6 molecular switch functions. Cancer Cell 2002, 1:469-478.
30. Cyr JL, Brown GD, Stroop J, Heinen CD. The predicted truncation from a cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex. Mol Carcinog 2012, 51:647-658.
31. Ollila S, Dermadi Bebek D, Jiricny J, Nystrom M. Mechanisms of pathogenicity in human MSH2 missense mutants. Hum Mutat 2008, 29:1355-1363.
32. Lutzen A, de Wind N, Georgijevic D, Nielsen F, Rasmussen L. Functional analysis of HNPCC-related missense mutations in MSH2. Mutat Res 2008, 645:44-55.
33. Clark AB, Cook ME, Tran HT, Gordenin DA, Resnick MA, Kunkel TA. Functional analysis of human MutSalpha and MutSbeta complexes in yeast. Nucleic Acids Res 1999, 27:736-742.
34. Drotschmann K, Clark AB, Tran HT, Resnick MA, Gordenin DA, Kunkel TA. Mutator phenotypes of yeast strains heterozygous for mutations in the MSH2 gene. Proc Natl Acad Sci U S A 1999, 96:2970-2975.
35. Drotschmann K, Clark AB, Kunkel TA. Mutator phenotypes of common polymorphisms and missense mutations in MSH2. Curr Biol 1999, 9:907-910.
36. Javaid S, Manohar M, Punja N, Mooney A, Ottesen JJ, Poirier MG, Fishel R. Nucleosome Remodeling by hMSH2-hMSH6. Mol Cell 2009, 36:1086-1094.
37. Li F, Tian L, Gu L, Li G-M. Evidence that nucleosomes inhibit mismatch repair in eukaryotic cells. J Biol Chem 2009, 284:33056-33061.
38. Schopf B, Bregenhorn S, Quivy JP, Kadyrov FA, Almouzni G, Jiricny J. Interplay between mismatch repair and chromatin assembly. Proc Natl Acad Sci U S A 2012, 109:1895-1900.
39. Trojan J, Zeuzem S, Randolph A, Hemmerle C, Brieger A, Raedle J, Plotz G, Jiricny J, Marra G. Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. Gastroenterology 2002, 122:211-219.
40. Perera S, Bapat B. The MLH1 variants p.Arg265Cys and p.Lys618Ala affect protein stability while p.Leu749Gln affects heterodimer formation. Hum Mutat 2008, 29:332.
41. Takahashi M, Shimodaira H, Andreutti-Zaugg C, Iggo R, Kolodner RD, Ishioka C. Functional Analysis of Human MLH1 Variants Using Yeast and In vitro Mismatch Repair Assays. Cancer Res 2007, 67:4595-4604.
42. Buermeyer AB, Wilson-Van Patten C, Baker SM, Liskay RM. The human MLH1 cDNA complements DNA mismatch repair defects in Mlh1- deficient mouse embryonic fibroblasts. Cancer Res 1999, 59:538-541.
43. Mohd AB, Palama B, Nelson SE, Tomer G, Nguyen M, Huo X, Buermeyer AB. Truncation of the C-terminus of human MLH1 blocks intracellular stabilization of PMS2 and disrupts DNA mismatch repair. DNA Repair 2006, 5:347-361.
44. Drummond JT, Anthoney A, Brown R, Modrich P. Cisplatin and Adriamycin Resistance Are Associated with MutLα and Mismatch Repair Deficiency in an Ovarian Tumor Cell Line. J Biol Chem 1996, 271:19645-19648.
45. Ollila S, Sarantaus L, Kariola R, Chan P, Hampel H, Holinski-Feder E, Macrae F, Kohonen-Corish M, Gerdes A-M, Peltomäki P, et al. Pathogenicity of MSH2 Missense Mutations Is Typically Associated With Impaired Repair Capability of the Mutated Protein. Gastroenterology 2006, 131:1408-1417.
46. Marra G, Iaccarino I, Lettieri T, Roscilli G, Delmastro P, Jiricny J. Mismatch repair deficiency associated with overexpression of the MSH3 gene. Proc Natl Acad Sci U S A 1998, 95:8568-8573.
47. Koi M, Umar A, Chauhan DP, Cherian SP, Carethers JM, Kunkel TA, Boland CR. Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N'-nitro-N-nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation. Cancer Res 1994, 54:4308-4312.
48. Umar A, Koi M, Risinger J, Glaab W, Tindall K, Kolodner R, Boland C, Barrett J, Kunkel T. Correction of hypermutability, N-methyl-N'-nitro-N-nitrosoguanidine resistance, and defective DNA mismatch repair by introducing chromosome 2 into human tumor cells with mutations in MSH2 and MSH6. Cancer Res 1997, 57:3949-3955.
49. Lettieri T, Marra G, Aquilina G, Bignami M, Crompton NEA, Palombo F, Jiricny J. Effect of hMSH6 cDNA expression on the phenotype of mismatch repair-deficient colon cancer cell line HCT15. Carcinogenesis 1999, 20:373-382.
50. Cejka P, Stojic L, Mojas N, Russell AM, Heinimann K, Cannavo E, di Pietro M, Marra G, Jiricny J. Methylation-induced G2/M arrest requires a full complement of the mismatch repair protein hMLH1. EMBO J 2003, 22:2245-2254.
51. Jager AC, Rasmussen M, Bisgaard HC, Singh KK, Nielsen FC, Rasmussen LJ. HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence assembly of hMutLalpha and hMLH1-hEXO1 complexes. Oncogene 2001, 20:3590-3595.
52. Raevaara TE, Korhonen M, Lohi H, Hampel H, Lynch E, Lonnqvist KE, Holinski-Feder E, Sutter C, McKinnon W, Duraisamy S, et al. Functional Significance and Clinical Phenotype of Nontruncating Mismatch Repair Variants of MLH1. Gastroenterology 2005, 129:537-549.
53. Brieger A, Plotz G, Hinrichsen I, Passmann S, Adam R, Zeuzem S. C-terminal fluorescent labeling impairs functionality of DNA mismatch repair proteins. PLoS One 2012, 7:e31863.
54. Zhang H, Richards B, Wilson T, Lloyd M, Cranston A, Thorburn A, Fishel R, Meuth M. Apoptosis induced by overexpression of hMSH2 or hMLH1. Cancer Res 1999, 59:3021-3027.
55. Claij N, Te Riele H. Methylation tolerance in mismatch repair proficient cells with low MSH2 protein level. Oncogene 2002, 21:2873-2879.
56. Wielders EAL, Dekker RJ, Holt I, Morris GE, te Riele H. Characterization of MSH2 variants by endogenous gene modification in mouse embryonic stem cells. Hum Mutat 2011, 32:389-396.
57. Rago C, Vogelstein B, Bunz F. Genetic knockouts and knockins in human somatic cells. Nat Protocols 2007, 2:2734-2746.
58. Hockemeyer D, Soldner F, Beard C, Gao Q, Mitalipova M, DeKelver RC, Katibah GE, Amora R, Boydston EA, Zeitler B, et al. Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat Biotech 2009, 27:851-857.
59. Cermak T, Doyle EL, Christian M, Wang L, Zhang Y, Schmidt C, Baller JA, Somia NV, Bogdanove AJ, Voytas DF. Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting. Nucleic Acids Res 2011, 39:e82.
60. Knudsen NO, Andersen SD, Lutzen A, Nielsen FC, Rasmussen LJ. Nuclear translocation contributes to regulation of DNA excision repair activities. DNA Repair 2009, 8:682-689.
61. Aebi S, Kurdi-Haidar B, Gordon R, Cenni B, Zheng H, Fink D, Christen RD, Boland CR, Koi M, Fishel R, Howell SB. Loss of DNA mismatch repair in acquired resistance to cisplatin. Cancer Res 1996, 56:3087-3090.
62. Branch P, Hampson R, Karran P. DNA mismatch binding defects, DNA damage tolerance, and mutator phenotypes in human colorectal carcinoma cell lines. Cancer Res 1995, 55:2304-2309.
63. Cejka P, Marra G, Hemmerle C, Cannavo E, Storchova Z, Jiricny J. Differential Killing of Mismatch Repair-Deficient and -Proficient Cells: Towards the Therapy of Tumors with Microsatellite Instability. Cancer Res 2003, 63:8113-8117.
64. de Wind N, Dekker M, Berns A, Radman M, te Riele H. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 1995, 82:321-330.
65. Kat A, Thilly WG, Fang WH, Longley MJ, Li GM, Modrich P. An alkylation-tolerant, mutator human cell line is deficient in strand-specific mismatch repair. Proc Natl Acad Sci U S A 1993, 90:6424-6428.
66. Stojic L, Mojas N, Cejka P, di Pietro M, Ferrari S, Marra G, Jiricny J. Mismatch repair-dependent G2 checkpoint induced by low doses of SN1 type methylating agents requires the ATR kinase. Genes Dev 2004, 18:1331-1344.
67. Toft NJ, Winton DJ, Kelly J, Howard LA, Dekker M, te Riele H, Arends MJ, Wyllie AH, Margison GP, Clarke AR. Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine. Proc Natl Acad Sci U S A 1999, 96:3911-3915.
68. Wu J, Gu L, Wang H, Geacintov NE, Li GM. Mismatch repair processing of carcinogen-DNA adducts triggers apoptosis. Mol Cell Biol 1999, 19:8292-8301.
69. Heinen CD, Schmutte C, Fishel R. DNA Repair and Tumorigenesis: Lessons from Hereditary Cancer Syndromes. Cancer Biol Ther 2002, 1:477-485.
70. Hollenbach JP, Resch AM, Palakodeti D, Graveley BR, Heinen CD. Loss of DNA mismatch repair imparts a selective advantage in planarian adult stem cells. PLoS One 2011, 6:e21808.
71. Lin DP, Wang Y, Scherer SJ, Clark AB, Yang K, Avdievich E, Jin B, Werling U, Parris T, Kurihara N, et al. An Msh2 Point Mutation Uncouples DNA Mismatch Repair and Apoptosis. Cancer Res 2004, 64:517-522.
72. Yang G, Scherer SJ, Shell SS, Yang K, Kim M, Lipkin M, Kucherlapati R, Kolodner RD, Edelmann W. Dominant effects of an Msh6 missense mutation on DNA repair and cancer susceptibility. Cancer Cell 2004, 6:139-150.
73. Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, Cabrera BL, Goel A, Arnold CA, Miyai K, Boland CR. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 2004, 126:394-401.
74. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, et al. Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer. N Engl J Med 2003, 349:247-257.
75. Jover R, Zapater P, Castells A, Llor X, Andreu M, Cubiella J, Pinol V, Xicola RM, Bujanda L, Rene JM, et al. Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy on colorectal cancer. Gut 2006, 55:848-855.
76. Benatti P, Gafa R, Barana D, Marino M, Scarselli A, Pedroni M, Maestri I, Guerzoni L, Roncucci L, Menigatti M, et al. Microsatellite Instability and Colorectal Cancer Prognosis. Clin Cancer Res 2005, 11:8332-8340.
77. Mastrocola AS, Heinen CD. Lynch syndrome-associated mutations in MSH2 alter DNA repair and checkpoint response functions in vivo. Hum Mutat 2010, 31:E1699-E1708.
78. Zhou B, Huang C, Yang J, Lu J, Dong Q, Sun LZ. Preparation of heteroduplex EGFP plasmid for in vivo mismatch repair activity assay. Anal Biochem 2009, 1:167-169.
79. Blasi MF, Ventura I, Aquilina G, Degan P, Bertario L, Bassi C, Radice P, Bignami M. A Human Cell-Based Assay to Evaluate the Effects of Alterations in the MLH1 Mismatch Repair Gene. Cancer Res 2006, 66:9036-9044.
80. Gammie AE, Erdeniz N, Beaver J, Devlin B, Nanji A, Rose MD. Functional characterization of pathogenic human MSH2 missense mutations in Saccharomyces cerevisiae. Genetics 2007, 177:707-721.
81. Polaczek P, Putzke AP, Leong K, Bitter GA. Functional genetic tests of DNA mismatch repair protein activity in Saccharomyces cerevisiae. Gene 1998, 213:159-167.
82. Shimodaira H, Filosi N, Shibata H, Suzuki T, Radice P, Kanamaru R, Friend SH, Kolodner RD, Ishioka C. Functional analysis of human MLH1 mutations in Saccharomyces cerevisiae. Nat Genet 1998, 19:384-389.
83. Wanat JJ, Singh N, Alani E. The effect of genetic background on the function of Saccharomyces cerevisiae mlh1 alleles that correspond to HNPCC missense mutations. Hum Mol Genet 2007, 16:445-452.
84. Shcherbakova PV, Kunkel TA. Mutator Phenotypes Conferred by MLH1 Overexpression and by Heterozygosity for mlh1 Mutations. Mol Cell Biol 1999, 19:3177-3183.
85. Pang Q, Prolla TA, Liskay RM. Functional domains of the Saccharomyces cerevisiae Mlh1p and Pms1p DNA mismatch repair proteins and their relevance to human hereditary nonpolyposis colorectal cancer-associated mutations. Mol Cell Biol 1997, 17:4465-4473.
86. Ellison AR, Lofing J, Bitter GA. Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae. Hum Mol Genet 2001, 10:1889-1900.
87. Ellison AR, Lofing J, Bitter GA. Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain. Nucl Acids Res 2004, 32:5321-5338.
88. Vogelsang M, Comino A, Zupanec N, Hudler P, Komel R. Assessing pathogenicity of MLH1 variants by co-expression of human MLH1 and PMS2 genes in yeast. BMC Cancer 2009, 9:382.
89. Sharp A, Pichert G, Lucassen A, Eccles D. RNA analysis reveals splicing mutations and loss of expression defects in MLH1 and BRCA1. Hum Mutat 2004, 24:272.
90. Pagenstecher C, Wehner M, Friedl W, Rahner N, Aretz S, Friedrichs N, Sengteller M, Henn W, Buettner R, Propping P, Mangold E. Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants. Hum Genet 2006, 119:9-22.
91. Auclair J, Busine M, Navarro C, Ruano E, Montmain G, Desseigne F, Saurin J, Lasset C, Bonadona V, Giraud S, et al. Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. Hum Mutat 2006, 27:145-154.
92. Tournier I, Vezain M, Martins A, Charbonnier F, Baert-Desurmont S, Olschwang S, Wang Q, Buisine MP, Soret J, Tazi J, et al. A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. Hum Mutat 2008, 29:1412-1424.
93. Nystrom-Lahti M, Perrera C, Raschle M, Panyushkina-Seiler E, Marra G, Curci A, Quaresima B, Costanzo F, D'Urso M, Venuta S, Jiricny J. Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer. Genes Chromosomes Cancer 2002, 33:160-167.
94. Martinez SL, Kolodner RD. Functional analysis of human mismatch repair gene mutations identifies weak alleles and polymorphisms capable of polygenic interactions. Proc Natl Acad Sci 2010, 107:5070-5075.
95. Duraturo F, Liccardo R, Cavallo A, Rosa MD, Grosso M, Izzo P. Association of low-risk MSH3 and MSH2 variant alleles with Lynch syndrome: Probability of synergistic effects. Int J Cancer 2011, 129:1643-1650.
96. Ou J, Niessen R, Vonk J, Westers H, Hofstra R, Sijmons R. A database to support the interpretation of human mismatch repair gene variants. Hum Mutat 2008, 29:1337-1341.
97. Plotz G, Welsch C, Giron-Monzon L, Friedhoff P, Albrecht M, Piiper A, Biondi R, Lengauer T, Zeuzem S, Raedle J. Mutations in the MutSalpha interaction interface of MLH1 can abolish DNA mismatch repair. Nucl Acids Res 2006, 34:6574-6586.
98. Hofstra RM, Spurdle AB, Eccles D, Foulkes WD, de Wind N, Hoogerbrugge N, Hogervorst FB. Tumor characteristics as an analytic tool for classifying genetic variants of uncertain clinical significance. Hum Mutat 2008, 29:1292-1303.