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DNA mismatch repair protein Mlh1 (MutL protein homolog 1)

 MLH1_HUMAN              Reviewed;         756 AA.
P40692; B4DI13; B4DQ11; E9PCU2;
01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
01-FEB-1995, sequence version 1.
30-AUG-2017, entry version 200.
RecName: Full=DNA mismatch repair protein Mlh1;
AltName: Full=MutL protein homolog 1;
Name=MLH1; Synonyms=COCA2;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
PubMed=8145827; DOI=10.1038/368258a0;
Bronner C.E., Baker S.M., Morrison P.T., Warren G., Smith L.G.,
Lescoe M.K., Kane M.F., Earibino C., Lipford J., Lindblom A.,
Tannergaard P., Bollag R.J., Godwin A.R., Ward D.C., Nordenskjoeld M.,
Fishel R., Kolodner R.D., Liskay R.M.;
"Mutation in the DNA mismatch repair gene homologue hMLH1 is
associated with hereditary non-polyposis colon cancer.";
Nature 368:258-261(1994).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
TISSUE=Gall bladder;
PubMed=8128251; DOI=10.1126/science.8128251;
Papadopoulos N., Nicolaides N.C., Wei Y.-F., Ruben S.M., Carter K.C.,
Rosen C.A., Haseltine W.A., Fleischmann R.D., Fraser C.M., Adams M.D.,
Venter J.C., Hamilton S.R., Petersen G.M., Watson P., Lynch H.T.,
Peltomaeki P., Mecklin J.-P., de la Chapelle A., Kinzler K.W.,
Vogelstein B.;
"Mutation of a mutL homolog in hereditary colon cancer.";
Science 263:1625-1629(1994).
[3]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
PubMed=7812952;
Kolodner R.D., Hall N.R., Lipford J.R., Kane M.F., Morrison P.,
Finan P.J., Burn J., Chapman P., Earabino C., Merchant E.,
Bishop D.T.;
"Structure of the human MLH1 locus and analysis of a large hereditary
nonpolyposis colorectal carcinoma kindred for mlh1 mutations.";
Cancer Res. 55:242-248(1995).
[4]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS HNPCC2 LEU-542;
PRO-574; VAL-582 AND THR-618.
PubMed=7757073; DOI=10.1093/hmg/4.2.237;
Han H.-J., Maruyama M., Baba S., Park J.-G., Nakamura Y.;
"Genomic structure of human mismatch repair gene, hMLH1, and its
mutation analysis in patients with hereditary non-polyposis colorectal
cancer (HNPCC).";
Hum. Mol. Genet. 4:237-242(1995).
[5]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS VAL-32; MET-213 AND
VAL-219.
NIEHS SNPs program;
Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
TISSUE=Brain, Corpus callosum, Kidney, and Substantia nigra;
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[7]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=16641997; DOI=10.1038/nature04728;
Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
Gibbs R.A.;
"The DNA sequence, annotation and analysis of human chromosome 3.";
Nature 440:1194-1198(2006).
[8]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
[9]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Placenta;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[10]
IDENTIFICATION OF MLH1 AS MEMBER OF BASC.
PubMed=10783165;
Wang Y., Cortez D., Yazdi P., Neff N., Elledge S.J., Qin J.;
"BASC, a super complex of BRCA1-associated proteins involved in the
recognition and repair of aberrant DNA structures.";
Genes Dev. 14:927-939(2000).
[11]
INTERACTION WITH MBD4.
PubMed=10097147; DOI=10.1073/pnas.96.7.3969;
Bellacosa A., Cicchillitti L., Schepis F., Riccio A., Yeung A.T.,
Matsumoto Y., Golemis E.A., Genuardi M., Neri G.;
"MED1, a novel human methyl-CpG-binding endonuclease, interacts with
DNA mismatch repair protein MLH1.";
Proc. Natl. Acad. Sci. U.S.A. 96:3969-3974(1999).
[12]
INTERACTION WITH EXO1 AND PMS2, CHARACTERIZATION OF VARIANTS HNPCC2
PRO-574; LYS-616 DEL; LEU-659 AND THR-681, AND CHARACTERIZATION OF
VARIANT MMRCS LYS-616 DEL.
PubMed=11427529; DOI=10.1074/jbc.M102670200;
Schmutte C., Sadoff M.M., Shim K.-S., Acharya S., Fishel R.;
"The interaction of DNA mismatch repair proteins with human
exonuclease I.";
J. Biol. Chem. 276:33011-33018(2001).
[13]
INTERACTION WITH EXO1, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF
VARIANT MET-117.
PubMed=11429708; DOI=10.1038/sj.onc.1204467;
Jaeger A.C., Rasmussen M., Bisgaard H.C., Singh K.K., Nielsen F.C.,
Rasmussen L.J.;
"HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence
assembly of hMutLalpha and hMLH1-hEXO1 complexes.";
Oncogene 20:3590-3595(2001).
[14]
INTERACTION WITH EXO1.
PubMed=12414623;
Sun X., Zheng L., Shen B.;
"Functional alterations of human exonuclease 1 mutants identified in
atypical hereditary nonpolyposis colorectal cancer syndrome.";
Cancer Res. 62:6026-6030(2002).
[15]
INTERACTION WITH EXO1, AND SUBCELLULAR LOCATION.
PubMed=14676842; DOI=10.1038/sj.onc.1207265;
Nielsen F.C., Jaeger A.C., Luetzen A., Bundgaard J.R., Rasmussen L.J.;
"Characterization of human exonuclease 1 in complex with mismatch
repair proteins, subcellular localization and association with PCNA.";
Oncogene 23:1457-1468(2004).
[16]
INVOLVEMENT IN MRTES.
PubMed=8751876;
Bapat B., Xia L., Madlensky L., Mitri A., Tonin P., Narod S.A.,
Gallinger S.;
"The genetic basis of Muir-Torre syndrome includes the hMLH1 locus.";
Am. J. Hum. Genet. 59:736-739(1996).
[17]
FUNCTION.
PubMed=16873062; DOI=10.1016/j.cell.2006.05.039;
Kadyrov F.A., Dzantiev L., Constantin N., Modrich P.;
"Endonucleolytic function of MutLalpha in human mismatch repair.";
Cell 126:297-308(2006).
[18]
FUNCTION.
PubMed=18206974; DOI=10.1016/j.molcel.2007.10.030;
Sacho E.J., Kadyrov F.A., Modrich P., Kunkel T.A., Erie D.A.;
"Direct visualization of asymmetric adenine nucleotide-induced
conformational changes in MutL alpha.";
Mol. Cell 29:112-121(2008).
[19]
REVIEW.
PubMed=16188885; DOI=10.1074/jbc.M509701200;
Constantin N., Dzantiev L., Kadyrov F.A., Modrich P.;
"Human mismatch repair: reconstitution of a nick-directed
bidirectional reaction.";
J. Biol. Chem. 280:39752-39761(2005).
[20]
REVIEW.
PubMed=16873053; DOI=10.1016/j.cell.2006.07.003;
Jiricny J.;
"MutLalpha: at the cutting edge of mismatch repair.";
Cell 126:239-241(2006).
[21]
REVIEW.
PubMed=18157157; DOI=10.1038/cr.2007.115;
Li G.M.;
"Mechanisms and functions of DNA mismatch repair.";
Cell Res. 18:85-98(2008).
[22]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-477, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=18669648; DOI=10.1073/pnas.0805139105;
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
Elledge S.J., Gygi S.P.;
"A quantitative atlas of mitotic phosphorylation.";
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
[23]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-477, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Leukemic T-cell;
PubMed=19690332; DOI=10.1126/scisignal.2000007;
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
Rodionov V., Han D.K.;
"Quantitative phosphoproteomic analysis of T cell receptor signaling
reveals system-wide modulation of protein-protein interactions.";
Sci. Signal. 2:RA46-RA46(2009).
[24]
INTERACTION WITH MTMR15.
PubMed=20603073; DOI=10.1016/j.molcel.2010.06.023;
Smogorzewska A., Desetty R., Saito T.T., Schlabach M., Lach F.P.,
Sowa M.E., Clark A.B., Kunkel T.A., Harper J.W., Colaiacovo M.P.,
Elledge S.J.;
"A genetic screen identifies FAN1, a Fanconi anemia-associated
nuclease necessary for DNA interstrand crosslink repair.";
Mol. Cell 39:36-47(2010).
[25]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[26]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-477, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21406692; DOI=10.1126/scisignal.2001570;
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
Blagoev B.;
"System-wide temporal characterization of the proteome and
phosphoproteome of human embryonic stem cell differentiation.";
Sci. Signal. 4:RS3-RS3(2011).
[27]
ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS
SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=22223895; DOI=10.1074/mcp.M111.015131;
Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C.,
Meinnel T., Giglione C.;
"Comparative large-scale characterisation of plant vs. mammal proteins
reveals similar and idiosyncratic N-alpha acetylation features.";
Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
[28]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-477, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma, and Erythroleukemia;
PubMed=23186163; DOI=10.1021/pr300630k;
Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
Mohammed S.;
"Toward a comprehensive characterization of a human cancer cell
phosphoproteome.";
J. Proteome Res. 12:260-271(2013).
[29]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-477, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Liver;
PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D.,
Wang L., Ye M., Zou H.;
"An enzyme assisted RP-RPLC approach for in-depth analysis of human
liver phosphoproteome.";
J. Proteomics 96:253-262(2014).
[30]
X-RAY CRYSTALLOGRAPHY (2.16 ANGSTROMS) OF 486-751.
Dombrovsky L., Dong A., Wernimont A., Loppnau P., Bountra C.,
Weigelt J., Arrowsmith C.H., Edwards A.M., Min J., Wu H.;
"Crystal structure of MutL protein homolog 1 isoform 1.";
Submitted (MAR-2011) to the PDB data bank.
[31]
X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 3-196 IN COMPLEX WITH ADP
AND MAGNESIUM IONS.
PubMed=26249686; DOI=10.1107/S2053230X15010183;
Wu H., Zeng H., Lam R., Tempel W., Kerr I.D., Min J.;
"Structure of the human MLH1 N-terminus: implications for
predisposition to Lynch syndrome.";
Acta Crystallogr. F 71:981-985(2015).
[32]
CHARACTERIZATION OF VARIANTS HNPCC2 CYS-31; LYS-37; HIS-38; LYS-38;
PHE-44; ARG-67; PRO-109; PRO-111; MET-117; CYS-265; SER-265; GLN-443;
PRO-550; GLY-578; PHE-582; ASP-589; ALA-618; CYS-646; LEU-648; LEU-654
AND PRO-659, CHARACTERIZATION OF VARIANTS GLY-93; VAL-219; SER-403;
ASN-406 AND MET-716, AND FUNCTION.
PubMed=20020535; DOI=10.1002/humu.21180;
Drost M., Zonneveld J.B., van Dijk L., Morreau H., Tops C.M.,
Vasen H.F., Wijnen J.T., de Wind N.;
"A cell-free assay for the functional analysis of variants of the
mismatch repair protein MLH1.";
Hum. Mutat. 31:247-253(2010).
[33]
CHARACTERIZATION OF VARIANTS HNPCC2 LEU-28; SER-29; 45-THR--ILE-47
DELINS CYS-PHE; GLU-63; ARG-67; GLU-71 DEL; ARG-77; VAL-80; GLU-84;
ARG-107; ARG-155; GLY-185; PRO-247; PRO-329; ILE-330 DEL; GLN-443;
ALA-460; PRO-550; 578-GLU--GLU-632 DEL; ASP-589; VAL-612 DEL; LYS-616
DEL; ALA-618; THR-618; 633-GLU--GLU-663 DEL; CYS-646; LEU-648;
SER-648; LEU-654; GLN-659; PRO-659; THR-681 AND TRP-687,
CHARACTERIZATION OF VARIANTS GLY-93; MET-213; VAL-219 AND MET-716,
SUBCELLULAR LOCATION, AND FUNCTION.
PubMed=21120944; DOI=10.1002/humu.21409;
Kansikas M., Kariola R., Nystroem M.;
"Verification of the three-step model in assessing the pathogenicity
of mismatch repair gene variants.";
Hum. Mutat. 32:107-115(2011).
[34]
VARIANT MMRCS LYS-616 DEL.
PubMed=7661930; DOI=10.1056/NEJM199503303321302;
Hamilton S.R., Liu B., Parsons R.E., Papadopoulos N., Jen J.,
Powell S.M., Krush A.J., Berk T., Cohen Z., Tetu B., Burger P.C.,
Wood P.A., Taqi F., Booker S.V., Petersen G.M., Offerhaus G.J.A.,
Tersmette A.C., Giardiello F.M., Vogelstein B., Kinzler K.W.;
"The molecular basis of Turcot's syndrome.";
N. Engl. J. Med. 332:839-847(1995).
[35]
VARIANT HNPCC2 LYS-616 DEL.
PubMed=8571956;
Wijnen J., Khan P.M., Vasen H., Menko F., van der Klift H.,
van den Broek M., van Leeuwen-Cornelisse I., Nagengast F.,
Meijers-Heijboer E.J., Lindhout D., Griffioen G., Cats A.,
Kleibeuker J., Varesco L., Bertario L., Bisgaard M.-L., Mohr J.,
Kolodner R.D., Fodde R.;
"Majority of hMLH1 mutations responsible for hereditary nonpolyposis
colorectal cancer cluster at the exonic region 15-16.";
Am. J. Hum. Genet. 58:300-307(1996).
[36]
VARIANTS HNPCC2 MET-117 AND LEU-226.
PubMed=8566964; DOI=10.1007/BF02265276;
Maliaka Y.K., Chudina A.P., Belev N.F., Alday P., Bochkov N.P.,
Buerstedde J.-M.;
"CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC
mutations.";
Hum. Genet. 97:251-255(1996).
[37]
VARIANTS HNPCC2 LYS-616 DEL AND THR-618, AND VARIANT CRC THR-492.
PubMed=8872463; DOI=10.1093/hmg/5.9.1245;
Moslein G., Tester D.J., Lindor N.M., Honchel R., Cunningham J.M.,
French A.J., Halling K.C., Schwab M., Goretzki P., Thibodeau S.N.;
"Microsatellite instability and mutation analysis of hMSH2 and hMLH1
in patients with sporadic, familial and hereditary colorectal
cancer.";
Hum. Mol. Genet. 5:1245-1252(1996).
[38]
VARIANTS HNPCC2 CYS-217; LEU-542; PRO-549 AND PRO-574.
PubMed=8797773; DOI=10.1093/jnci/88.18.1317;
Han H.-J., Yuan Y., Ku J.-L., Oh J.-H., Won Y.-J., Kang K.J.,
Kim K.Y., Kim S., Kim C.Y., Kim J.-P., Oh N.-G., Lee K.H., Choe K.J.,
Nakamura Y., Park J.-G.;
"Germline mutations of hMLH1 and hMSH2 genes in Korean hereditary
nonpolyposis colorectal cancer.";
J. Natl. Cancer Inst. 88:1317-1319(1996).
[39]
VARIANTS LEU-ASN-HIS-37 INS AND ASP-384.
PubMed=8609062; DOI=10.1111/j.1349-7006.1996.tb03151.x;
Kobayashi K., Matsushima M., Koi S., Saito H., Sagae S., Kudo R.,
Nakamura Y.;
"Mutational analysis of mismatch repair genes, hMLH1 and hMSH2, in
sporadic endometrial carcinomas with microsatellite instability.";
Jpn. J. Cancer Res. 87:141-145(1996).
[40]
VARIANTS HNPCC2 LYS-62; SER-64; LYS-616 DEL; ALA-618 AND PRO-659,
CHARACTERIZATION OF VARIANT HNPCC2 LYS-62, AND FUNCTION.
PubMed=9311737; DOI=10.1086/514847;
Wijnen J., Khan P.M., Vasen H., van der Klift H., Mulder A.,
van Leeuwen-Cornelisse I., Bakker B., Losekoot M., Moeller P.,
Fodde R.;
"Hereditary nonpolyposis colorectal cancer families not complying with
the Amsterdam criteria show extremely low frequency of mismatch-
repair-gene mutations.";
Am. J. Hum. Genet. 61:329-335(1997).
[41]
VARIANT HNPCC2 LYS-616 DEL, AND VARIANT HIS-265.
PubMed=8993976;
DOI=10.1002/(SICI)1098-2264(199701)18:1<8::AID-GCC2>3.0.CO;2-7;
Viel A., Genuardi M., Capozzi E., Leonardi F., Bellacosa A.,
Paravatou-Petsotas M., Pomponi M.G., Fornasarig M., Percesepe A.,
Roncucci L., Tamassia M.G., Benatti P., Ponz de Leon M., Valenti A.,
Covino M., Anti M., Foletto M., Boiocchi M., Neri G.;
"Characterization of MSH2 and MLH1 mutations in Italian families with
hereditary nonpolyposis colorectal cancer.";
Genes Chromosomes Cancer 18:8-18(1997).
[42]
VARIANTS CRC GLU-54; VAL-244 AND GLN-325, AND VARIANTS VAL-219 AND
ASN-406.
PubMed=9087566;
DOI=10.1002/(SICI)1098-2264(199704)18:4<269::AID-GCC4>3.3.CO;2-9;
Wu Y., Nystroem-Lahti M., Osinga J., Looman M.W.G., Peltomaeki P.,
Aaltonen L.A., de la Chapelle A., Hofstra R.M.W., Buys C.H.C.M.;
"MSH2 and MLH1 mutations in sporadic replication error-positive
colorectal carcinoma as assessed by two-dimensional DNA
electrophoresis.";
Genes Chromosomes Cancer 18:269-278(1997).
[43]
VARIANTS HNPCC2 PRO-128 AND ASP-244, AND VARIANT VAL-219.
PubMed=9218993;
DOI=10.1002/(SICI)1098-2264(199707)19:3<135::AID-GCC1>3.3.CO;2-X;
Pensotti V., Radice P., Presciuttini S., Calistri D., Gazzoli I.,
Grimalt Perez A.P., Mondini P., Buonsanti G., Sala P., Rossetti C.,
Ranzani G.N., Bertario L., Pierotti M.A.;
"Mean age of tumor onset in hereditary nonpolyposis colorectal cancer
(HNPCC) families correlates with the presence of mutations in DNA
mismatch repair genes.";
Genes Chromosomes Cancer 19:135-142(1997).
[44]
VARIANT HNPCC2 626-SER-THR-627.
PubMed=9048925; DOI=10.1007/s004390050343;
Beck N.E., Tomlinson I.P.M., Homfray T., Frayling I., Hodgson S.V.,
Harocopos C.J., Bodmer W.F.;
"Use of SSCP analysis to identify germline mutations in HNPCC families
fulfilling the Amsterdam criteria.";
Hum. Genet. 99:219-224(1997).
[45]
VARIANT HNPCC2 PRO-329.
PubMed=9272156; DOI=10.1007/s004390050517;
Wang Y., Friedl W., Lamberti C., Ruelfs C., Kruse R., Propping P.;
"Hereditary nonpolyposis colorectal cancer: causative role of a
germline missense mutation in the hMLH1 gene confirmed by the
independent occurrence of the same somatic mutation in tumour
tissue.";
Hum. Genet. 100:362-364(1997).
[46]
VARIANT HNPCC2 ARG-67, AND VARIANT VAL-219.
PubMed=9067757;
DOI=10.1002/(SICI)1098-1004(1997)9:2<164::AID-HUMU9>3.0.CO;2-9;
Sasaki S., Tokino T., Miyatsu T., Muto T., Nakamura Y.;
"Mutational analysis of the hMLH1 gene using an automated two-
dimensional DNA typing system.";
Hum. Mutat. 9:164-171(1997).
[47]
REVIEW ON VARIANTS.
PubMed=9259192;
DOI=10.1002/(SICI)1098-1004(1997)10:2<89::AID-HUMU1>3.3.CO;2-K;
Papadopoulos N., Lindblom A.;
"Molecular basis of HNPCC: mutations of MMR genes.";
Hum. Mutat. 10:89-99(1997).
[48]
VARIANT HNPCC2 LEU-28.
PubMed=9298827;
DOI=10.1002/(SICI)1098-1004(1997)10:3<241::AID-HUMU12>3.0.CO;2-#;
Wehner M., Buschhausen L., Lamberti C., Kruse R., Caspari R.,
Propping P., Friedl W.;
"Hereditary nonpolyposis colorectal cancer (HNPCC): eight novel
germline mutations in hMSH2 or hMLH1 genes.";
Hum. Mutat. 10:241-244(1997).
[49]
VARIANTS HNPCC2 GLY-182; THR-295 AND THR-551.
PubMed=9399661;
DOI=10.1002/(SICI)1097-0215(19971210)73:6<831::AID-IJC11>3.0.CO;2-7;
Wang Q., Desseigne F., Lasset C., Saurin J.-C., Navarro C., Yagci T.,
Keser I., Bagci H., Luleci G., Gelen T., Chayvialle J.-A.,
Puisieux A., Ozturk M.;
"Germline hMSH2 and hMLH1 gene mutations in incomplete HNPCC
families.";
Int. J. Cancer 73:831-836(1997).
[50]
VARIANT CRC TYR-77, AND VARIANT VAL-219.
PubMed=9032648; DOI=10.1136/jmg.34.1.39;
Tomlinson I.P.M., Beck N.E., Homfray T., Harocopos C.J., Bodmer W.F.;
"Germline HNPCC gene variants have little influence on the risk for
sporadic colorectal cancer.";
J. Med. Genet. 34:39-42(1997).
[51]
VARIANTS HNPCC2 PHE-44 AND THR-441.
PubMed=9326924; DOI=10.1038/ng1097-135;
Hackman P., Tannergaerd P., Osei-Mensa S., Chen J., Kane M.F.,
Kolodner R.D., Lambert B., Hellgren D., Lindblom A.;
"A human compound heterozygote for two MLH1 missense mutations.";
Nat. Genet. 17:135-136(1997).
[52]
VARIANTS HNPCC2, AND VARIANTS.
PubMed=9718327; DOI=10.1086/301996;
Farrington S.M., Lin-Goerke J., Ling J., Wang Y., Burczak J.D.,
Robbins D.J., Dunlop M.G.;
"Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients
and controls.";
Am. J. Hum. Genet. 63:749-759(1998).
[53]
VARIANT CRC GLY-268.
PubMed=9611074;
Liu T., Wahlberg S., Rubio C., Holmberg E., Groenberg H., Lindblom A.;
"DGGE screening of mutations in mismatch repair genes (hMSH2 and
hMLH1) in 34 Swedish families with colorectal cancer.";
Clin. Genet. 53:131-135(1998).
[54]
VARIANT HNPCC2 CYS-217.
PubMed=9559627; DOI=10.1007/BF02235756;
Yuan Y., Han H.-J., Zheng S., Park J.-G.;
"Germline mutations of hMLH1 and hMSH2 genes in patients with
suspected hereditary nonpolyposis colorectal cancer and sporadic
early-onset colorectal cancer.";
Dis. Colon Rectum 41:434-440(1998).
[55]
VARIANT ASP-384, AND ASSOCIATION WITH HNPCC.
PubMed=9526167; DOI=10.1159/000022786;
Wang Y., Friedl W., Lamberti C., Noethen M.M., Kruse R., Propping P.;
"A novel missense mutation in the DNA mismatch repair gene hMLH1
present among East Asians but not among Europeans.";
Hum. Hered. 48:87-91(1998).
[56]
VARIANT HNPCC2 LYS-69.
PubMed=10627141;
DOI=10.1002/(SICI)1098-1004(1998)12:1<73::AID-HUMU20>3.0.CO;2-F;
Herfarth K.K.-F., Ogunbiyi O.A., Moley J.F., Kodner I.J.,
Wells S.A. Jr., Goodfellow P.J.;
"Four new mutations in the DNA mismatch repair gene MLH1 in colorectal
cancers with microsatellite instability.";
Hum. Mutat. 12:73-73(1998).
[57]
VARIANTS HNPCC2 ARG-77 AND PRO-193.
PubMed=10660333;
Panariello L., Scarano M.I., de Rosa M., Capasso L., Renda A.,
Riegler G., Rossi G.B., Salvatore F., Izzo P.;
"hMLH1 mutations in hereditary nonpolyposis colorectal cancer
kindreds.";
Hum. Mutat. 12:216-217(1998).
[58]
VARIANT GLY-93.
PubMed=10671064;
DOI=10.1002/(SICI)1098-1004(1998)12:6<433::AID-HUMU13>3.0.CO;2-J;
Quaresima B., Grandinetti C., Baudi F., Tassone P., Barbieri V.,
Conforti S., Avvedimento E.V., Costanzo F., Venuta S.;
"Hereditary nonpolyposis colorectal cancer: identification of novel
germline mutations in two kindreds not fulfilling the Amsterdam
criteria.";
Hum. Mutat. 12:433-433(1998).
[59]
VARIANTS HNPCC2 ARG-67; ILE-262 DEL; THR-551 AND PHE-565, AND VARIANTS
VAL-219 AND MET-716.
PubMed=9833759;
DOI=10.1002/(SICI)1097-0215(19981209)78:6<680::AID-IJC3>3.0.CO;2-U;
Hutter P., Couturier A., Membrez V., Joris F., Sappino A.-P.,
Chappuis P.O.;
"Excess of hMLH1 germline mutations in Swiss families with hereditary
non-polyposis colorectal cancer.";
Int. J. Cancer 78:680-684(1998).
[60]
VARIANTS HNPCC2 ARG-67; ARG-117 AND GLU-485, AND VARIANT VAL-219.
PubMed=10375096;
DOI=10.1002/(SICI)1097-0142(19990615)85:12<2512::AID-CNCR4>3.0.CO;2-G;
Heinimann K., Scott R.J., Buerstedde J.-M., Weber W., Siebold K.,
Attenhofer M., Mueller H., Dobbie Z.;
"Influence of selection criteria on mutation detection in patients
with hereditary nonpolyposis colorectal cancer.";
Cancer 85:2512-2518(1999).
[61]
VARIANT HNPCC2 TRP-67.
PubMed=9927034;
Wang Q., Lasset C., Desseigne F., Frappaz D., Bergeron C., Navarro C.,
Ruano E., Puisieux A.;
"Neurofibromatosis and early onset of cancers in hMLH1-deficient
children.";
Cancer Res. 59:294-297(1999).
[62]
VARIANTS HIS-265; ALA-326; PRO-385; ASN-406; THR-618 AND MET-716.
PubMed=10573010; DOI=10.1038/sj.ejhg.5200363;
Genuardi M., Carrara S., Anti M., Ponz de Leon M., Viel A.;
"Assessment of pathogenicity criteria for constitutional missense
mutations of the hereditary nonpolyposis colorectal cancer genes MLH1
and MSH2.";
Eur. J. Hum. Genet. 7:778-782(1999).
[63]
VARIANTS HNPCC2 LEU-28; GLU-84 AND PRO-329.
PubMed=10323887; DOI=10.1136/gut.44.6.839;
Lamberti C., Kruse R., Ruelfs C., Caspari R., Wang Y., Jungck M.,
Mathiak M., Malayeri H.R.H., Friedl W., Sauerbruch T., Propping P.;
"Microsatellite instability, a useful diagnostic tool to select
patients at high risk for hereditary non-polyposis colorectal cancer:
a study in different groups of patients with colorectal cancer.";
Gut 44:839-843(1999).
[64]
VARIANTS HNPCC2 TRP-67; MET-117; GLY-182 AND LYS-616 DEL, AND VARIANT
HNPCC TRP-755.
PubMed=10480359; DOI=10.1007/s004399900064;
Wang Q., Lasset C., Desseigne F., Saurin J.-C., Maugard C.,
Navarro C., Ruano E., Descos L., Trillet-Lenoir V., Bosset J.-F.,
Puisieux A.;
"Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and
hMSH6 genes in 75 French kindreds with nonpolyposis colorectal
cancer.";
Hum. Genet. 105:79-85(1999).
[65]
VARIANT CRC GLY-578, AND VARIANT HNPCC2 ALA-618.
PubMed=10598809; DOI=10.1007/s004390051127;
Liu T., Tannergaerd P., Hackman P., Rubio C., Kressner U.,
Lindmark G., Hellgren D., Lambert B., Lindblom A.;
"Missense mutations in hMLH1 associated with colorectal cancer.";
Hum. Genet. 105:437-441(1999).
[66]
VARIANT HNPCC2 PHE-25, AND VARIANT TYR-718.
PubMed=10386556; DOI=10.1001/jama.281.24.2316;
Weber T.K., Chin H.-M., Rodriguez-Bigas M., Keitz B., Gilligan R.,
O'Malley L., Urf E., Diba N., Pazik J., Petrelli N.J.;
"Novel hMLH1 and hMSH2 germline mutations in African Americans with
colorectal cancer.";
JAMA 281:2316-2320(1999).
[67]
VARIANT HNPCC2 TYR-264.
PubMed=10413423; DOI=10.1093/jnci/91.14.1221;
Chan T.L., Yuen S.T., Chung L.P., Ho J.W.C., Kwan K.Y.M., Chan A.S.Y.,
Ho J.C.Y., Leung S.Y., Wyllie A.H.;
"Frequent microsatellite instability and mismatch repair gene
mutations in young Chinese patients with colorectal cancer.";
J. Natl. Cancer Inst. 91:1221-1226(1999).
[68]
VARIANTS HNPCC2 VAL-111 AND PRO-588, AND VARIANTS VAL-219 AND ASP-384.
PubMed=10777691; DOI=10.1006/bbrc.2000.2547;
Nomura S., Sugano K., Kashiwabara H., Taniguchi T., Fukayama N.,
Fujita S., Akasu T., Moriya Y., Ohhigashi S., Kakizoe T., Sekiya T.;
"Enhanced detection of deleterious and other germline mutations of
hMSH2 and hMLH1 in Japanese hereditary nonpolyposis colorectal cancer
kindreds.";
Biochem. Biophys. Res. Commun. 271:120-129(2000).
[69]
VARIANTS HNPCC2 HIS-607; ALA-618 AND LEU-659, AND VARIANT MET-213.
PubMed=10713887; DOI=10.1038/sj.ejhg.5200393;
Fidalgo P., Almeida M.R., West S., Gaspar C., Maia L., Wijnen J.,
Albuquerque C., Curtis A., Cravo M., Fodde R., Leitao C.N., Burn J.;
"Detection of mutations in mismatch repair genes in Portuguese
families with hereditary non-polyposis colorectal cancer (HNPCC) by a
multi-method approach.";
Eur. J. Hum. Genet. 8:49-53(2000).
[70]
VARIANT CRC ARG-260, AND VARIANT HNPCC2 VAL-304.
PubMed=10882759; DOI=10.1136/jmg.37.7.e7;
Montera M., Resta N., Simone C., Guanti G., Marchese C., Civitelli S.,
Mancini A., Pozzi S., De Salvo L., Bruzzone D., Donadini A., Romio L.,
Mareni C.;
"Mutational germline analysis of hMSH2 and hMLH1 genes in early onset
colorectal cancer patients.";
J. Med. Genet. 37:E7-E7(2000).
[71]
ERRATUM.
Montera M., Resta N., Simone C., Guanti G., Marchese C., Civitelli S.,
Mancini A., Pozzi S., De Salvo L., Bruzzone D., Donadini A., Romio L.,
Mareni C.;
J. Med. Genet. 40:472-472(2003).
[72]
VARIANTS GASTRIC CANCER ARG-106; GLN-109 AND LYS-635, VARIANTS HNPCC2
GLY-234; ILE-321; HIS-485 AND ALA-631, AND VARIANT CRC ILE-472.
PubMed=12132870;
Kim J.C., Kim H.C., Roh S.A., Koo K.H., Lee D.H., Yu C.S., Lee J.H.,
Kim T.W., Lee H.I., Beck N.E., Bodmer W.F.;
"hMLH1 and hMSH2 mutations in families with familial clustering of
gastric cancer and hereditary non-polyposis colorectal cancer.";
Cancer Detect. Prev. 25:503-510(2001).
[73]
VARIANT HIS-607.
PubMed=11369138; DOI=10.1016/S0304-3835(01)00448-7;
Stone J.G., Coleman G., Gusterson B., Marossy A., Lakhani S.R.,
Ward A., Nash A., McKinna A., A'Hern R., Stratton M.R., Houlston R.S.;
"Contribution of germline MLH1 and MSH2 mutations to lobular carcinoma
in situ of the breast.";
Cancer Lett. 167:171-174(2001).
[74]
INVOLVEMENT IN TUMORIGENESIS.
PubMed=11389087;
Vilkki S., Tsao J.-L., Loukola A., Poyhonen M., Vierimaa O., Herva R.,
Aaltonen L.A., Shibata D.;
"Extensive somatic microsatellite mutations in normal human tissue.";
Cancer Res. 61:4541-4544(2001).
[75]
VARIANTS HNPCC2 VAL-80; PRO-329; ARG-603; ALA-618; LEU-648 AND
PRO-662, AND VARIANT HNPCC ARG-689.
PubMed=11726306;
Mueller-Koch Y., Kopp R., Lohse P., Baretton G., Stoetzer A., Aust D.,
Daum J., Kerker B., Gross M., Dietmeier W., Holinski-Feder E.;
"Sixteen rare sequence variants of the hMLH1 and hMSH2 genes found in
a cohort of 254 suspected HNPCC (hereditary non-polyposis colorectal
cancer) patients: mutations or polymorphisms?";
Eur. J. Med. Res. 6:473-482(2001).
[76]
CHARACTERIZATION OF VARIANTS.
PubMed=11555625; DOI=10.1093/hmg/10.18.1889;
Ellison A.R., Lofing J., Bitter G.A.;
"Functional analysis of human MLH1 and MSH2 missense variants and
hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae.";
Hum. Mol. Genet. 10:1889-1900(2001).
[77]
VARIANT HNPCC2 ARG-751.
PubMed=11139242;
DOI=10.1002/1098-1004(2001)17:1<52::AID-HUMU6>3.0.CO;2-E;
Jakubowska A., Gorski B., Kurzawski G., Debniak T., Hadaczek P.,
Cybulski C., Kladny J., Oszurek O., Scott R.J., Lubinski J.;
"Optimization of experimental conditions for RNA-based sequencing of
MLH1 and MSH2 genes.";
Hum. Mutat. 17:52-60(2001).
[78]
VARIANTS HNPCC2 HIS-622 AND TRP-687.
PubMed=11748856; DOI=10.1002/humu.1240;
Godino J., de La Hoya M., Diaz-Rubio E., Benito M., Caldes T.;
"Eight novel germline MLH1 and MSH2 mutations in hereditary non-
polyposis colorectal cancer families from Spain.";
Hum. Mutat. 18:549-549(2001).
[79]
VARIANTS HNPCC2 SER-338; ARG-603; THR-618 AND TYR-718.
PubMed=12095971; DOI=10.1007/BF02573891;
Rossi B.M., Lopes A., Oliveira Ferreira F., Nakagawa W.T.,
Napoli Ferreira C.C., Casali Da Rocha J.C., Simpson C.C.,
Simpson A.J.G.;
"hMLH1 and hMSH2 gene mutation in Brazilian families with suspected
hereditary nonpolyposis colorectal cancer.";
Ann. Surg. Oncol. 9:555-561(2002).
[80]
VARIANTS HNPCC2 ASN-35; HIS-38; MET-117 AND ALA-618.
PubMed=12373605; DOI=10.1038/sj.bjc.6600565;
Gille J.J.P., Hogervorst F.B.L., Pals G., Wijnen J.T.,
van Schooten R.J., Dommering C.J., Meijer G.A., Craanen M.E.,
Nederlof P.M., de Jong D., McElgunn C.J., Schouten J.P., Menko F.H.;
"Genomic deletions of MSH2 and MLH1 in colorectal cancer families
detected by a novel mutation detection approach.";
Br. J. Cancer 87:892-897(2002).
[81]
VARIANTS VAL-219 AND VAL-655.
PubMed=12115348; DOI=10.1002/cncr.10606;
Baldinu P., Cossu A., Manca A., Satta M.P., Pisano M., Casula M.,
Dessole S., Pintus A., Tanda F., Palmieri G.;
"Microsatellite instability and mutation analysis of candidate genes
in unselected Sardinian patients with endometrial carcinoma.";
Cancer 94:3157-3168(2002).
[82]
CHARACTERIZATION OF VARIANTS HNPCC2 MET-117; GLY-185; CYS-217; ASP-244
AND ALA-326, AND CHARACTERIZATION OF VARIANTS VAL-219 AND HIS-265.
PubMed=11781295; DOI=10.1053/gast.2002.30296;
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 122:211-219(2002).
[83]
VARIANTS HNPCC2 CYS-385; HIS-607; THR-618 AND SER-648, AND VARIANT
MET-213.
PubMed=11839723; DOI=10.1136/gut.50.3.405;
Cravo M., Afonso A.J., Lage P., Albuquerque C., Maia L., Lacerda C.,
Fidalgo P., Chaves P., Cruz C., Nobre-Leitao C.;
"Pathogenicity of missense and splice site mutations in hMSH2 and
hMLH1 mismatch repair genes: implications for genetic testing.";
Gut 50:405-412(2002).
[84]
CHARACTERIZATION OF VARIANTS HNPCC2 ARG-77; ARG-107 AND PRO-659, AND
CHARACTERIZATION OF VARIANT GLY-93.
PubMed=11793442; DOI=10.1002/gcc.1225.abs;
Nystroem-Lahti M., Perrera C., Raeschle 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 33:160-167(2002).
[85]
VARIANT HNPCC2 PRO-662, AND VARIANT VAL-219.
PubMed=11754112; DOI=10.1002/humu.9004;
Krueger S., Plaschke J., Pistorius S., Jeske B., Haas S., Kraemer H.,
Hinterseher I., Bier A., Kreuz F.R., Theissig F., Saeger H.D.,
Schackert H.K.;
"Seven novel MLH1 and MSH2 germline mutations in hereditary
nonpolyposis colorectal cancer.";
Hum. Mutat. 19:82-82(2002).
[86]
VARIANTS HNPCC2 MET-117 AND PRO-247, AND VARIANTS VAL-219; ALA-618 AND
MET-716.
PubMed=12200596; DOI=10.1007/s00432-002-0361-2;
Ward R., Meldrum C., Williams R., Mokany E., Scott R., Turner J.,
Hawkins N., Burgess B., Groombridge C., Spigelman A.;
"Impact of microsatellite testing and mismatch repair protein
expression on the clinical interpretation of genetic testing in
hereditary non-polyposis colorectal cancer.";
J. Cancer Res. Clin. Oncol. 128:403-411(2002).
[87]
VARIANT HNPCC2 CYS-646, AND VARIANT ALA-618.
PubMed=11870161; DOI=10.1200/JCO.20.5.1203;
Scartozzi M., Bianchi F., Rosati S., Galizia E., Antolini A.,
Loretelli C., Piga A., Bearzi I., Cellerino R., Porfiri E.;
"Mutations of hMLH1 and hMSH2 in patients with suspected hereditary
nonpolyposis colorectal cancer: correlation with microsatellite
instability and abnormalities of mismatch repair protein expression.";
J. Clin. Oncol. 20:1203-1208(2002).
[88]
VARIANTS HNPCC2 PHE-19; LEU-28; MET-117; PRO-292; THR-681 AND TRP-687,
AND VARIANT VAL-219.
PubMed=12362047; DOI=10.1136/jmg.39.10.e65;
Kurzawski G., Suchy J., Kladny J., Safranow K., Jakubowska A.,
Elsakov P., Kucinskas V., Gardovski J., Irmejs A., Sibul H.,
Huzarski T., Byrski T., Debniak T., Cybulski C., Gronwald J.,
Oszurek O., Clark J., Gozdz S., Niepsuj S., Slomski R., Plawski A.,
Lacka-Wojciechowska A., Rozmiarek A., Fiszer-Maliszewska L.,
Bebenek M., Sorokin D., Stawicka M., Godlewski D., Richter P.,
Brozek I., Wysocka B., Jawien A., Banaszkiewicz Z., Kowalczyk J.,
Czudowska D., Goretzki P.E., Moeslein G., Lubinski J.;
"Germline MSH2 and MLH1 mutational spectrum in HNPCC families from
Poland and the Baltic States.";
J. Med. Genet. 39:E65-E65(2002).
[89]
VARIANTS HNPCC2 SER-29; ARG-67; LEU-185 AND ASP-244.
PubMed=12658575; DOI=10.1086/373963;
Wagner A., Barrows A., Wijnen J.T., van der Klift H., Franken P.F.,
Verkuijlen P., Nakagawa H., Geugien M., Jaghmohan-Changur S.,
Breukel C., Meijers-Heijboer H., Morreau H., van Puijenbroek M.,
Burn J., Coronel S., Kinarski Y., Okimoto R., Watson P., Lynch J.F.,
de la Chapelle A., Lynch H.T., Fodde R.;
"Molecular analysis of hereditary nonpolyposis colorectal cancer in
the United States: high mutation detection rate among clinically
selected families and characterization of an American founder genomic
deletion of the MSH2 gene.";
Am. J. Hum. Genet. 72:1088-1100(2003).
[90]
VARIANTS CRC 325-ARG--GLN-327 DEL; ARG-618 AND PRO-749.
PubMed=14504054; DOI=10.1093/annonc/mdg402;
Colombino M., Cossu A., Arba A., Manca A., Curci A., Avallone A.,
Comella G., Botti G., Scintu F., Amoruso M., D'Abbicco D.,
d'Agnessa M.R., Spanu A., Tanda F., Palmieri G.;
"Microsatellite instability and mutation analysis among southern
Italian patients with colorectal carcinoma: detection of different
alterations accounting for MLH1 and MSH2 inactivation in familial
cases.";
Ann. Oncol. 14:1530-1536(2003).
[91]
VARIANT HNPCC2 PRO-586.
PubMed=12655562; DOI=10.1002/humu.9121;
Kruger S., Plaschke J., Jeske B., Gorgens H., Pistorius S.R., Bier A.,
Kreuz F.R., Theissig F., Aust D.E., Saeger H.D., Schackert H.K.;
"Identification of six novel MSH2 and MLH1 germline mutations in
HNPCC.";
Hum. Mutat. 21:445-446(2003).
[92]
VARIANT CRC GLY-601.
PubMed=12655564; DOI=10.1002/humu.9123;
Chen-Shtoyerman R., Theodor L., Harmati E., Friedman E., Dacka S.,
Kopelman Y., Sternberg A., Zarivach R., Bar-Meir S., Fireman Z.;
"Genetic analysis of familial colorectal cancer in Israeli Arabs.";
Hum. Mutat. 21:446-447(2003).
[93]
VARIANTS HNPCC2 CYS-18; ASP-101; LYS-182; CYS-379; ARG-559 AND LYS-616
DEL.
PubMed=14635101; DOI=10.1002/humu.10291;
Taylor C.F., Charlton R.S., Burn J., Sheridan E., Taylor G.R.;
"Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary
non-polyposis colorectal cancer: identification of novel and recurrent
deletions by MLPA.";
Hum. Mutat. 22:428-433(2003).
[94]
VARIANT HNPCC2 SER-648.
PubMed=15139004; DOI=10.1002/gcc.20040;
Raevaara T.E., Gerdes A.-M., Loennqvist K.E., Tybjaerg-Hansen A.,
Abdel-Rahman W.M., Kariola R., Peltomaeki P., Nystroem-Lahti M.;
"HNPCC mutation MLH1 P648S makes the functional protein unstable, and
homozygosity predisposes to mild neurofibromatosis type 1.";
Genes Chromosomes Cancer 40:261-265(2004).
[95]
VARIANTS HNPCC2 CYS-217; GLY-282; LEU-542; PRO-542; PRO-549; PRO-574;
PRO-636; SER-640 AND MET-724.
PubMed=15365995; DOI=10.1002/humu.9277;
Shin Y.-K., Heo S.-C., Shin J.-H., Hong S.-H., Ku J.-L., Yoo B.-C.,
Kim I.-J., Park J.-G.;
"Germline mutations in MLH1, MSH2 and MSH6 in Korean hereditary non-
polyposis colorectal cancer families.";
Hum. Mutat. 24:351-351(2004).
[96]
ERRATUM.
Shin Y.K., Heo S.C., Shin J.H., Hong S.H., Ku J.L., Yoo B.C.,
Kim I.J., Park J.G.;
Hum. Mutat. 25:224-224(2005).
[97]
VARIANTS HNPCC2 GLY-41 AND ASN-VAL-PHE-HIS-ILE-719 INS.
PubMed=15365996; DOI=10.1002/humu.9278;
Krueger S., Bier A., Plaschke J., Hoehl R., Aust D.E., Kreuz F.R.,
Pistorius S.R., Saeger H.D., Rothhammer V., Al-Taie O.,
Schackert H.K.;
"Ten novel MSH2 and MLH1 germline mutations in families with HNPCC.";
Hum. Mutat. 24:351-352(2004).
[98]
VARIANTS HNPCC2 VAL-21; ARG-67; ASN-68 AND LYS-616 DEL.
PubMed=14961575; DOI=10.1002/ijc.11718;
Cederquist K., Emanuelsson M., Goeransson I., Holinski-Feder E.,
Mueller-Koch Y., Golovleva I., Groenberg H.;
"Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with
double primary cancers of the colorectum and the endometrium: a
population-based study in northern Sweden.";
Int. J. Cancer 109:370-376(2004).
[99]
ERRATUM.
Cederquist K., Emanuelsson M., Goransson I., Holinski-Feder E.,
Muller-Koch Y., Golovleva I., Gronberg H.;
Int. J. Cancer 115:1011-1011(2005).
[100]
INVOLVEMENT IN HNPCC2 BY EPIGENETIC INHERITANCE.
PubMed=15064764; DOI=10.1038/ng1342;
Suter C.M., Martin D.I.K., Ward R.L.;
"Germline epimutation of MLH1 in individuals with multiple cancers.";
Nat. Genet. 36:497-501(2004).
[101]
VARIANT CRC HIS-132.
PubMed=15184898; DOI=10.1038/ng1374;
Lipkin S.M., Rozek L.S., Rennert G., Yang W., Chen P.-C., Hacia J.,
Hunt N., Shin B., Fodor S., Kokoris M., Greenson J.K., Fearon E.,
Lynch H., Collins F., Gruber S.B.;
"The MLH1 D132H variant is associated with susceptibility to sporadic
colorectal cancer.";
Nat. Genet. 36:694-699(2004).
[102]
VARIANTS HNPCC2 LEU-28; 45-THR--PHE-47 DELINS CYS-PHE; GLU-63; ARG-67;
GLU-71 DEL; ARG-77; VAL-80; GLU-84; ARG-107; ARG-155; GLY-185;
PRO-247; PRO-329; ILE-330 DEL; PRO-550; ASP-589; VAL-612 DEL; LYS-616
DEL; LEU-648; SER-648; LEU-654 AND PRO-659, VARIANTS SER-29; GLY-93;
GLN-443; ALA-618; CYS-646; GLN-659; THR-681 AND MET-716,
CHARACTERIZATION OF VARIANTS HNPCC2 LEU-28; 45-THR--PHE-47 DELINS
CYS-PHE; GLU-63; ARG-67; GLU-71 DEL; ARG-77; VAL-80; GLU-84; ARG-107;
ARG-155; GLY-185; PRO-247; PRO-329; ILE-330 DEL; PRO-550; ASP-589;
VAL-612 DEL; LYS-616 DEL; THR-618; LEU-648; SER-648; LEU-654 AND
PRO-659, AND CHARACTERIZATION OF VARIANTS SER-29; GLY-93; MET-213;
VAL-219; GLN-443; ALA-618; CYS-646; GLN-659; THR-681 AND MET-716.
PubMed=16083711; DOI=10.1053/j.gastro.2005.06.005;
Raevaara T.E., Korhonen M.K., Lohi H., Hampel H., Lynch E.,
Loennqvist K.E., Holinski-Feder E., Sutter C., McKinnon W.,
Duraisamy S., Gerdes A.-M., Peltomaeki P., Kohonen-Corish M.,
Mangold E., Macrae F., Greenblatt M., de la Chapelle A., Nystroem M.;
"Functional significance and clinical phenotype of nontruncating
mismatch repair variants of MLH1.";
Gastroenterology 129:537-549(2005).
[103]
VARIANTS HNPCC2 LEU-28; LYS-35; ARG-67; VAL-111; MET-117; PRO-292;
THR-441; LYS-618 DEL; PRO-623; ILE-657 DEL; THR-681; TRP-687 AND
ARG-751.
PubMed=16451135; DOI=10.1111/j.1399-0004.2006.00550.x;
Kurzawski G., Suchy J., Lener M., Klujszo-Grabowska E., Kladny J.,
Safranow K., Jakubowska K., Jakubowska A., Huzarski T., Byrski T.,
Debniak T., Cybulski C., Gronwald J., Oszurek O., Oszutowska D.,
Kowalska E., Gozdz S., Niepsuj S., Slomski R., Plawski A.,
Lacka-Wojciechowska A., Rozmiarek A., Fiszer-Maliszewska L.,
Bebenek M., Sorokin D., Sasiadek M.M., Stembalska A., Grzebieniak Z.,
Kilar E., Stawicka M., Godlewski D., Richter P., Brozek I.,
Wysocka B., Limon J., Jawien A., Banaszkiewicz Z., Janiszewska H.,
Kowalczyk J., Czudowska D., Scott R.J., Lubinski J.;
"Germline MSH2 and MLH1 mutational spectrum including large
rearrangements in HNPCC families from Poland (update study).";
Clin. Genet. 69:40-47(2006).
[104]
VARIANT MMRCS ASN-35.
PubMed=17440981; DOI=10.1002/cncr.22697;
Rotterdam initiative on gastrointestinal hereditary tumors;
Poley J.-W., Wagner A., Hoogmans M.M.C.P., Menko F.H., Tops C.,
Kros J.M., Reddingius R.E., Meijers-Heijboer H., Kuipers E.J.,
Dinjens W.N.M.;
"Biallelic germline mutations of mismatch-repair genes: a possible
cause for multiple pediatric malignancies.";
Cancer 109:2349-2356(2007).
[105]
VARIANTS HNPCC2 LYS-102 AND GLN-474.
PubMed=17510385; DOI=10.1158/0008-5472.CAN-06-3509;
Takahashi M., Shimodaira H., Andreutti-Zaugg C., Iggo R.,
Kolodner R.D., Ishioka C.;
"Functional analysis of human MLH1 variants using yeast and in vitro
mismatch repair assays.";
Cancer Res. 67:4595-4604(2007).
[106]
INVOLVEMENT IN HNPCC2 BY GERMLINE EPIMUTATION.
PubMed=17301300; DOI=10.1056/NEJMoa064522;
Hitchins M.P., Wong J.J.L., Suthers G., Suter C.M., Martin D.I.K.,
Hawkins N.J., Ward R.L.;
"Inheritance of a cancer-associated MLH1 germ-line epimutation.";
N. Engl. J. Med. 356:697-705(2007).
[107]
VARIANTS CRC GLU-67 AND THR-681, AND VARIANTS ALA-22; GLY-93; SER-309;
ASN-406; HIS-607; ALA-618; ARG-689; MET-716; TYR-718 AND ARG-751.
PubMed=18033691; DOI=10.1002/humu.20635;
Barnetson R.A., Cartwright N., van Vliet A., Haq N., Drew K.,
Farrington S., Williams N., Warner J., Campbell H., Porteous M.E.,
Dunlop M.G.;
"Classification of ambiguous mutations in DNA mismatch repair genes
identified in a population-based study of colorectal cancer.";
Hum. Mutat. 29:367-374(2008).
[108]
VARIANT HNPCC2 ILE-330 DEL, AND VARIANTS HIS-41; ARG-67; ARG-77;
SER-98; SER-101; ASP-101; LYS-116; MET-117; ASN-126; MET-213; SER-215;
SER-216; PHE-260; CYS-265; HIS-265; ASP-320; ALA-326; ILE-330 DEL;
TRP-474; GLN-474; ASP-539; PRO-549; THR-551; ARG-585; ARG-603;
HIS-607; PRO-619; SER-640; LEU-640; VAL-655; SER-656; ARG-666; THR-681
AND ARG-689.
PubMed=18561205; DOI=10.1002/humu.20796;
Tournier I., Vezain M., Martins A., Charbonnier F.,
Baert-Desurmont S., Olschwang S., Wang Q., Buisine M.P., Soret J.,
Tazi J., Frebourg T., Tosi M.;
"A large fraction of unclassified variants of the mismatch repair
genes MLH1 and MSH2 is associated with splicing defects.";
Hum. Mutat. 29:1412-1424(2008).
[109]
VARIANTS HNPCC2 CYS-233 DEL AND TRP-389, CHARACTERIZATION OF VARIANTS
HNPCC2 LEU-28; LYS-37; HIS-38; LYS-38; PHE-44; ARG-67; PRO-109;
PRO-111; MET-117; CYS-233 DEL; CYS-265; TRP-389; GLN-443; PRO-550;
GLY-578; PHE-582; ASP-589; ALA-618; CYS-646; LEU-648; LEU-654; PRO-659
AND VAL-716 DEL, CHARACTERIZATION OF VARIANTS GLY-93; VAL-219;
SER-403; ASN-406 AND MET-716, INTERACTION WITH PMS2, INTERACTION WITH
EXO1, AND SUBCELLULAR LOCATION.
PubMed=22753075; DOI=10.1002/humu.22153;
Andersen S.D., Liberti S.E., Luetzen A., Drost M., Bernstein I.,
Nilbert M., Dominguez M., Nystroem M., Hansen T.V.,
Christoffersen J.W., Jaeger A.C., de Wind N., Nielsen F.C.,
Toerring P.M., Rasmussen L.J.;
"Functional characterization of MLH1 missense variants identified in
Lynch syndrome patients.";
Hum. Mutat. 33:1647-1655(2012).
-!- FUNCTION: Heterodimerizes with PMS2 to form MutL alpha, a
component of the post-replicative DNA mismatch repair system
(MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS
beta (MSH2-MSH6) binding to a dsDNA mismatch, then MutL alpha is
recruited to the heteroduplex. Assembly of the MutL-MutS-
heteroduplex ternary complex in presence of RFC and PCNA is
sufficient to activate endonuclease activity of PMS2. It
introduces single-strand breaks near the mismatch and thus
generates new entry points for the exonuclease EXO1 to degrade the
strand containing the mismatch. DNA methylation would prevent
cleavage and therefore assure that only the newly mutated DNA
strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts
physically with the clamp loader subunits of DNA polymerase III,
suggesting that it may play a role to recruit the DNA polymerase
III to the site of the MMR. Also implicated in DNA damage
signaling, a process which induces cell cycle arrest and can lead
to apoptosis in case of major DNA damages. Heterodimerizes with
MLH3 to form MutL gamma which plays a role in meiosis.
{ECO:0000269|PubMed:16873062, ECO:0000269|PubMed:18206974,
ECO:0000269|PubMed:20020535, ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:9311737}.
-!- SUBUNIT: Heterodimer of MLH1 and PMS2 (MutL alpha), MLH1 and PMS1
(MutL beta) or MLH1 and MLH3 (MutL gamma). Forms a ternary complex
with MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3). Part of the
BRCA1-associated genome surveillance complex (BASC), which
contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-
MRE11-NBS1 protein complex. This association could be a dynamic
process changing throughout the cell cycle and within subnuclear
domains. Interacts with MBD4. Interacts with EXO1 and MTMR15/FAN1.
{ECO:0000269|PubMed:10097147, ECO:0000269|PubMed:11427529,
ECO:0000269|PubMed:11429708, ECO:0000269|PubMed:12414623,
ECO:0000269|PubMed:14676842, ECO:0000269|PubMed:20603073,
ECO:0000269|PubMed:22753075}.
-!- INTERACTION:
P63261:ACTG1; NbExp=7; IntAct=EBI-744248, EBI-351292;
P07355:ANXA2; NbExp=7; IntAct=EBI-744248, EBI-352622;
P63010-2:AP2B1; NbExp=7; IntAct=EBI-744248, EBI-11529439;
Q9BX63:BRIP1; NbExp=11; IntAct=EBI-744248, EBI-3509650;
P07858:CTSB; NbExp=7; IntAct=EBI-744248, EBI-715062;
Q6NSI4:CXorf57; NbExp=6; IntAct=EBI-744248, EBI-8634209;
P17661:DES; NbExp=7; IntAct=EBI-744248, EBI-1055572;
Q5VWN6:FAM208B; NbExp=5; IntAct=EBI-744248, EBI-745958;
Q16658:FSCN1; NbExp=7; IntAct=EBI-744248, EBI-351076;
P52292:KPNA2; NbExp=3; IntAct=EBI-744248, EBI-349938;
P43361:MAGEA8; NbExp=5; IntAct=EBI-744248, EBI-10182930;
O95243-2:MBD4; NbExp=6; IntAct=EBI-744248, EBI-6448717;
P20585:MSH3; NbExp=3; IntAct=EBI-744248, EBI-1164205;
P15173:MYOG; NbExp=8; IntAct=EBI-744248, EBI-3906629;
Q969T7:NT5C3B; NbExp=3; IntAct=EBI-744248, EBI-2932564;
P54278:PMS2; NbExp=7; IntAct=EBI-744248, EBI-1162561;
P25786:PSMA1; NbExp=3; IntAct=EBI-744248, EBI-359352;
P26045:PTPN3; NbExp=4; IntAct=EBI-744248, EBI-1047946;
Q8NA61:SPERT; NbExp=4; IntAct=EBI-744248, EBI-741724;
Q8NA61-2:SPERT; NbExp=9; IntAct=EBI-744248, EBI-11524851;
Q13813:SPTAN1; NbExp=7; IntAct=EBI-744248, EBI-351450;
P62328:TMSB4X; NbExp=16; IntAct=EBI-744248, EBI-712598;
O94941:UBOX5; NbExp=3; IntAct=EBI-744248, EBI-751901;
O75152:ZC3H11A; NbExp=3; IntAct=EBI-744248, EBI-748480;
-!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11429708,
ECO:0000269|PubMed:14676842, ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=3;
Name=1;
IsoId=P40692-1; Sequence=Displayed;
Name=2;
IsoId=P40692-2; Sequence=VSP_045201;
Name=3;
IsoId=P40692-3; Sequence=VSP_047023;
Note=No experimental confirmation available.;
-!- TISSUE SPECIFICITY: Colon, lymphocytes, breast, lung, spleen,
testis, prostate, thyroid, gall bladder and heart.
-!- DISEASE: Hereditary non-polyposis colorectal cancer 2 (HNPCC2)
[MIM:609310]: An autosomal dominant disease associated with marked
increase in cancer susceptibility. It is characterized by a
familial predisposition to early-onset colorectal carcinoma (CRC)
and extra-colonic tumors of the gastrointestinal, urological and
female reproductive tracts. HNPCC is reported to be the most
common form of inherited colorectal cancer in the Western world.
Clinically, HNPCC is often divided into two subgroups. Type I is
characterized by hereditary predisposition to colorectal cancer, a
young age of onset, and carcinoma observed in the proximal colon.
Type II is characterized by increased risk for cancers in certain
tissues such as the uterus, ovary, breast, stomach, small
intestine, skin, and larynx in addition to the colon. Diagnosis of
classical HNPCC is based on the Amsterdam criteria: 3 or more
relatives affected by colorectal cancer, one a first degree
relative of the other two; 2 or more generation affected; 1 or
more colorectal cancers presenting before 50 years of age;
exclusion of hereditary polyposis syndromes. The term 'suspected
HNPCC' or 'incomplete HNPCC' can be used to describe families who
do not or only partially fulfill the Amsterdam criteria, but in
whom a genetic basis for colon cancer is strongly suspected.
{ECO:0000269|PubMed:10323887, ECO:0000269|PubMed:10375096,
ECO:0000269|PubMed:10386556, ECO:0000269|PubMed:10413423,
ECO:0000269|PubMed:10480359, ECO:0000269|PubMed:10598809,
ECO:0000269|PubMed:10627141, ECO:0000269|PubMed:10660333,
ECO:0000269|PubMed:10671064, ECO:0000269|PubMed:10713887,
ECO:0000269|PubMed:10777691, ECO:0000269|PubMed:10882759,
ECO:0000269|PubMed:11139242, ECO:0000269|PubMed:11427529,
ECO:0000269|PubMed:11726306, ECO:0000269|PubMed:11748856,
ECO:0000269|PubMed:11754112, ECO:0000269|PubMed:11781295,
ECO:0000269|PubMed:11793442, ECO:0000269|PubMed:11839723,
ECO:0000269|PubMed:11870161, ECO:0000269|PubMed:12095971,
ECO:0000269|PubMed:12132870, ECO:0000269|PubMed:12200596,
ECO:0000269|PubMed:12362047, ECO:0000269|PubMed:12373605,
ECO:0000269|PubMed:12655562, ECO:0000269|PubMed:12658575,
ECO:0000269|PubMed:14635101, ECO:0000269|PubMed:14961575,
ECO:0000269|PubMed:15064764, ECO:0000269|PubMed:15139004,
ECO:0000269|PubMed:15365995, ECO:0000269|PubMed:15365996,
ECO:0000269|PubMed:16083711, ECO:0000269|PubMed:16451135,
ECO:0000269|PubMed:17301300, ECO:0000269|PubMed:17510385,
ECO:0000269|PubMed:18561205, ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:21120944, ECO:0000269|PubMed:22753075,
ECO:0000269|PubMed:7757073, ECO:0000269|PubMed:8566964,
ECO:0000269|PubMed:8571956, ECO:0000269|PubMed:8797773,
ECO:0000269|PubMed:8872463, ECO:0000269|PubMed:8993976,
ECO:0000269|PubMed:9048925, ECO:0000269|PubMed:9067757,
ECO:0000269|PubMed:9218993, ECO:0000269|PubMed:9272156,
ECO:0000269|PubMed:9298827, ECO:0000269|PubMed:9311737,
ECO:0000269|PubMed:9326924, ECO:0000269|PubMed:9399661,
ECO:0000269|PubMed:9559627, ECO:0000269|PubMed:9718327,
ECO:0000269|PubMed:9833759, ECO:0000269|PubMed:9927034,
ECO:0000269|Ref.5}. Note=The disease is caused by mutations
affecting the gene represented in this entry.
-!- DISEASE: Mismatch repair cancer syndrome (MMRCS) [MIM:276300]: An
autosomal recessive, rare, childhood cancer predisposition
syndrome encompassing a broad tumor spectrum. This includes
hematological malignancies, central nervous system tumors, Lynch
syndrome-associated malignancies such as colorectal tumors as well
as multiple intestinal polyps, embryonic tumors and
rhabdomyosarcoma. Multiple cafe-au-lait macules, a feature
reminiscent of neurofibromatosis type 1, are often found as first
manifestation of the underlying cancer. Areas of skin
hypopigmentation have also been reported in MMRCS patients.
{ECO:0000269|PubMed:11427529, ECO:0000269|PubMed:17440981,
ECO:0000269|PubMed:7661930}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- DISEASE: Muir-Torre syndrome (MRTES) [MIM:158320]: Rare autosomal
dominant disorder characterized by sebaceous neoplasms and
visceral malignancy. {ECO:0000269|PubMed:8751876}. Note=The
disease is caused by mutations affecting the gene represented in
this entry.
-!- DISEASE: Note=Defects in MLH1 may contribute to lobular carcinoma
in situ (LCIS), a non-invasive neoplastic disease of the breast.
-!- DISEASE: Endometrial cancer (ENDMC) [MIM:608089]: A malignancy of
endometrium, the mucous lining of the uterus. Most endometrial
cancers are adenocarcinomas, cancers that begin in cells that make
and release mucus and other fluids. Note=Disease susceptibility is
associated with variations affecting the gene represented in this
entry.
-!- DISEASE: Note=Some epigenetic changes can be transmitted unchanged
through the germline (termed 'epigenetic inheritance'). Evidence
that this mechanism occurs in humans is provided by the
identification of individuals in whom 1 allele of the MLH1 gene is
epigenetically silenced throughout the soma (implying a germline
event). These individuals are affected by HNPCC but does not have
identifiable mutations in MLH1, even though it is silenced, which
demonstrates that an epimutation can phenocopy a genetic disease.
-!- DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease
characterized by malignant lesions arising from the inner wall of
the large intestine (the colon) and the rectum. Genetic
alterations are often associated with progression from
premalignant lesion (adenoma) to invasive adenocarcinoma. Risk
factors for cancer of the colon and rectum include colon polyps,
long-standing ulcerative colitis, and genetic family history.
{ECO:0000269|PubMed:10598809, ECO:0000269|PubMed:10882759,
ECO:0000269|PubMed:12132870, ECO:0000269|PubMed:12655564,
ECO:0000269|PubMed:14504054, ECO:0000269|PubMed:15184898,
ECO:0000269|PubMed:18033691, ECO:0000269|PubMed:8872463,
ECO:0000269|PubMed:9032648, ECO:0000269|PubMed:9087566,
ECO:0000269|PubMed:9611074}. Note=Disease susceptibility is
associated with variations affecting the gene represented in this
entry.
-!- SIMILARITY: Belongs to the DNA mismatch repair MutL/HexB family.
{ECO:0000305}.
-!- WEB RESOURCE: Name=Hereditary non-polyposis colorectal cancer db;
URL="http://www.nfdht.nl/";
-!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
and Haematology;
URL="http://atlasgeneticsoncology.org/Genes/MLH1ID149ch3p21.html";
-!- WEB RESOURCE: Name=NIEHS-SNPs;
URL="http://egp.gs.washington.edu/data/mlh1/";
-!- WEB RESOURCE: Name=Colon cancer gene variant databases MutL
homolog 1 (E.coli) (MLH1); Note=Leiden Open Variation Database
(LOVD);
URL="http://chromium.lovd.nl/LOVD2/colon_cancer/home.php?select_db=MLH1";
-----------------------------------------------------------------------
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EMBL; U07343; AAC50285.1; -; mRNA.
EMBL; U07418; AAA17374.1; -; mRNA.
EMBL; U40978; AAA82079.1; -; Genomic_DNA.
EMBL; U40960; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40961; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40962; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40963; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40964; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40965; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40966; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40967; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40968; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40969; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40970; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40971; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40972; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40973; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40974; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40975; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40976; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U40977; AAA82079.1; JOINED; Genomic_DNA.
EMBL; U17857; AAA85687.1; -; Genomic_DNA.
EMBL; U17839; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17840; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17841; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17842; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17843; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17844; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17845; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17846; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17847; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17848; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17849; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17851; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17852; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17853; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17854; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17855; AAA85687.1; JOINED; Genomic_DNA.
EMBL; U17856; AAA85687.1; JOINED; Genomic_DNA.
EMBL; AY217549; AAO22994.1; -; Genomic_DNA.
EMBL; AK295359; BAG58325.1; -; mRNA.
EMBL; AK298324; BAG60576.1; -; mRNA.
EMBL; AK298583; BAG60773.1; -; mRNA.
EMBL; AK316074; BAH14445.1; -; mRNA.
EMBL; AK316264; BAH14635.1; -; mRNA.
EMBL; AC006583; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AC011816; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; CH471055; EAW64483.1; -; Genomic_DNA.
EMBL; BC006850; AAH06850.1; -; mRNA.
CCDS; CCDS2663.1; -. [P40692-1]
CCDS; CCDS54562.1; -. [P40692-3]
CCDS; CCDS54563.1; -. [P40692-2]
PIR; S43085; S43085.
RefSeq; NP_000240.1; NM_000249.3. [P40692-1]
RefSeq; NP_001161089.1; NM_001167617.1. [P40692-3]
RefSeq; NP_001161090.1; NM_001167618.1. [P40692-2]
RefSeq; NP_001161091.1; NM_001167619.1. [P40692-2]
RefSeq; NP_001245200.1; NM_001258271.1.
RefSeq; NP_001245202.1; NM_001258273.1. [P40692-2]
RefSeq; NP_001245203.1; NM_001258274.1. [P40692-2]
RefSeq; XP_005265220.1; XM_005265163.1. [P40692-2]
RefSeq; XP_005265221.1; XM_005265164.1. [P40692-2]
UniGene; Hs.195364; -.
PDB; 3RBN; X-ray; 2.16 A; A/B=486-751.
PDB; 4P7A; X-ray; 2.30 A; A=1-347.
PDBsum; 3RBN; -.
PDBsum; 4P7A; -.
ProteinModelPortal; P40692; -.
SMR; P40692; -.
BioGrid; 110438; 144.
DIP; DIP-27601N; -.
IntAct; P40692; 148.
MINT; MINT-257265; -.
STRING; 9606.ENSP00000231790; -.
iPTMnet; P40692; -.
PhosphoSitePlus; P40692; -.
BioMuta; MLH1; -.
DMDM; 730028; -.
EPD; P40692; -.
MaxQB; P40692; -.
PaxDb; P40692; -.
PeptideAtlas; P40692; -.
PRIDE; P40692; -.
DNASU; 4292; -.
Ensembl; ENST00000231790; ENSP00000231790; ENSG00000076242. [P40692-1]
Ensembl; ENST00000435176; ENSP00000402564; ENSG00000076242. [P40692-3]
Ensembl; ENST00000455445; ENSP00000398272; ENSG00000076242. [P40692-2]
Ensembl; ENST00000458205; ENSP00000402667; ENSG00000076242. [P40692-2]
Ensembl; ENST00000536378; ENSP00000444286; ENSG00000076242. [P40692-2]
Ensembl; ENST00000539477; ENSP00000443665; ENSG00000076242. [P40692-2]
GeneID; 4292; -.
KEGG; hsa:4292; -.
UCSC; uc003cgl.4; human. [P40692-1]
CTD; 4292; -.
DisGeNET; 4292; -.
GeneCards; MLH1; -.
GeneReviews; MLH1; -.
HGNC; HGNC:7127; MLH1.
HPA; CAB013294; -.
HPA; CAB070868; -.
HPA; HPA052707; -.
HPA; HPA060714; -.
MalaCards; MLH1; -.
MIM; 114500; phenotype.
MIM; 120436; gene.
MIM; 158320; phenotype.
MIM; 276300; phenotype.
MIM; 608089; phenotype.
MIM; 609310; phenotype.
neXtProt; NX_P40692; -.
OpenTargets; ENSG00000076242; -.
Orphanet; 252202; Constitutional mismatch repair deficiency syndrome.
Orphanet; 144; Hereditary nonpolyposis colon cancer.
Orphanet; 587; Muir-Torre syndrome.
Orphanet; 99817; Non-polyposis Turcot syndrome.
PharmGKB; PA240; -.
eggNOG; KOG1979; Eukaryota.
eggNOG; COG0323; LUCA.
GeneTree; ENSGT00800000124177; -.
HOGENOM; HOG000176000; -.
HOVERGEN; HBG006374; -.
InParanoid; P40692; -.
KO; K08734; -.
OMA; PWKWTVE; -.
OrthoDB; EOG091G02EP; -.
PhylomeDB; P40692; -.
TreeFam; TF300493; -.
Reactome; R-HSA-5358565; Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha).
Reactome; R-HSA-5358606; Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta).
Reactome; R-HSA-5545483; Defective Mismatch Repair Associated With MLH1.
Reactome; R-HSA-5632987; Defective Mismatch Repair Associated With PMS2.
Reactome; R-HSA-6796648; TP53 Regulates Transcription of DNA Repair Genes.
Reactome; R-HSA-912446; Meiotic recombination.
SIGNOR; P40692; -.
ChiTaRS; MLH1; human.
EvolutionaryTrace; P40692; -.
GeneWiki; MLH1; -.
GenomeRNAi; 4292; -.
PMAP-CutDB; P40692; -.
PRO; PR:P40692; -.
Proteomes; UP000005640; Chromosome 3.
Bgee; ENSG00000076242; -.
CleanEx; HS_MLH1; -.
ExpressionAtlas; P40692; baseline and differential.
Genevisible; P40692; HS.
GO; GO:0005712; C:chiasma; IBA:GO_Central.
GO; GO:0005715; C:late recombination nodule; IEA:Ensembl.
GO; GO:0001673; C:male germ cell nucleus; IEA:Ensembl.
GO; GO:0016020; C:membrane; IDA:UniProtKB.
GO; GO:0032389; C:MutLalpha complex; IBA:GO_Central.
GO; GO:0005654; C:nucleoplasm; IDA:HPA.
GO; GO:0005634; C:nucleus; IC:HGNC.
GO; GO:0000795; C:synaptonemal complex; IBA:GO_Central.
GO; GO:0005524; F:ATP binding; IEA:InterPro.
GO; GO:0016887; F:ATPase activity; IBA:GO_Central.
GO; GO:0003682; F:chromatin binding; IEA:Ensembl.
GO; GO:0032137; F:guanine/thymine mispair binding; IEA:Ensembl.
GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; IEA:Ensembl.
GO; GO:0016321; P:female meiosis chromosome segregation; IEA:Ensembl.
GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IEA:Ensembl.
GO; GO:0045190; P:isotype switching; IEA:Ensembl.
GO; GO:0007060; P:male meiosis chromosome segregation; IEA:Ensembl.
GO; GO:0043060; P:meiotic metaphase I plate congression; IEA:Ensembl.
GO; GO:0051257; P:meiotic spindle midzone assembly; IEA:Ensembl.
GO; GO:0045141; P:meiotic telomere clustering; IEA:Ensembl.
GO; GO:0006298; P:mismatch repair; IGI:MGI.
GO; GO:0045950; P:negative regulation of mitotic recombination; IEA:Ensembl.
GO; GO:0000289; P:nuclear-transcribed mRNA poly(A) tail shortening; IEA:Ensembl.
GO; GO:0048477; P:oogenesis; IEA:Ensembl.
GO; GO:0048298; P:positive regulation of isotype switching to IgA isotypes; IEA:Ensembl.
GO; GO:0048304; P:positive regulation of isotype switching to IgG isotypes; IEA:Ensembl.
GO; GO:0000712; P:resolution of meiotic recombination intermediates; IEA:Ensembl.
GO; GO:0016446; P:somatic hypermutation of immunoglobulin genes; IBA:GO_Central.
GO; GO:0007283; P:spermatogenesis; IEA:Ensembl.
GO; GO:0007129; P:synapsis; IEA:Ensembl.
Gene3D; 3.30.230.10; -; 1.
Gene3D; 3.30.565.10; -; 1.
InterPro; IPR013507; DNA_mismatch_repair_C.
InterPro; IPR014762; DNA_mismatch_repair_CS.
InterPro; IPR002099; DNA_mismatch_repair_fam.
InterPro; IPR003594; HATPase_C.
InterPro; IPR032189; Mlh1_C.
InterPro; IPR020568; Ribosomal_S5_D2-typ_fold.
InterPro; IPR014721; Ribosomal_S5_D2-typ_fold_subgr.
Pfam; PF01119; DNA_mis_repair; 1.
Pfam; PF16413; Mlh1_C; 1.
SMART; SM01340; DNA_mis_repair; 1.
SUPFAM; SSF54211; SSF54211; 1.
SUPFAM; SSF55874; SSF55874; 1.
TIGRFAMs; TIGR00585; mutl; 1.
PROSITE; PS00058; DNA_MISMATCH_REPAIR_1; 1.
1: Evidence at protein level;
3D-structure; Acetylation; Alternative splicing; ATP-binding;
Cell cycle; Complete proteome; Disease mutation; DNA damage;
DNA repair; Hereditary nonpolyposis colorectal cancer;
Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism;
Reference proteome; Tumor suppressor.
INIT_MET 1 1 Removed. {ECO:0000244|PubMed:22223895}.
CHAIN 2 756 DNA mismatch repair protein Mlh1.
/FTId=PRO_0000178000.
NP_BIND 82 84 ATP. {ECO:0000244|PDB:4P7A,
ECO:0000305|PubMed:26249686}.
NP_BIND 100 104 ATP. {ECO:0000244|PDB:4P7A,
ECO:0000305|PubMed:26249686}.
REGION 410 650 Interaction with EXO1.
{ECO:0000269|PubMed:11427529,
ECO:0000269|PubMed:11429708,
ECO:0000269|PubMed:12414623,
ECO:0000269|PubMed:14676842,
ECO:0000269|PubMed:22753075}.
BINDING 38 38 ATP. {ECO:0000244|PDB:4P7A,
ECO:0000305|PubMed:26249686}.
BINDING 63 63 ATP. {ECO:0000244|PDB:4P7A,
ECO:0000305|PubMed:26249686}.
MOD_RES 2 2 N-acetylserine.
{ECO:0000244|PubMed:22223895}.
MOD_RES 477 477 Phosphoserine.
{ECO:0000244|PubMed:18669648,
ECO:0000244|PubMed:19690332,
ECO:0000244|PubMed:21406692,
ECO:0000244|PubMed:23186163,
ECO:0000244|PubMed:24275569}.
VAR_SEQ 1 241 Missing (in isoform 2).
{ECO:0000303|PubMed:14702039}.
/FTId=VSP_045201.
VAR_SEQ 1 101 MSFVAGVIRRLDETVVNRIAAGEVIQRPANAIKEMIENCLD
AKSTSIQVIVKEGGLKLIQIQDNGTGIRKEDLDIVCERFTT
SKLQSFEDLASISTYGFRG -> MAF (in isoform
3). {ECO:0000303|PubMed:14702039}.
/FTId=VSP_047023.
VARIANT 18 18 R -> C (in HNPCC2; dbSNP:rs367654552).
{ECO:0000269|PubMed:14635101}.
/FTId=VAR_022663.
VARIANT 19 19 I -> F (in HNPCC2; unknown pathological
significance; dbSNP:rs63750648).
{ECO:0000269|PubMed:12362047}.
/FTId=VAR_043383.
VARIANT 21 21 A -> V (in HNPCC2; dbSNP:rs63750706).
{ECO:0000269|PubMed:14961575}.
/FTId=VAR_043384.
VARIANT 22 22 G -> A (in dbSNP:rs41295280).
{ECO:0000269|PubMed:18033691}.
/FTId=VAR_038023.
VARIANT 25 25 I -> F (in HNPCC2; dbSNP:rs63749838).
{ECO:0000269|PubMed:10386556}.
/FTId=VAR_043385.
VARIANT 28 28 P -> L (in HNPCC2; loss of protein
expression; normal interaction with PMS2
and EXO1; decreased mismatch repair
activity; no effect on nuclear
localization; dbSNP:rs63750792).
{ECO:0000269|PubMed:10323887,
ECO:0000269|PubMed:12362047,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:16451135,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075,
ECO:0000269|PubMed:9298827}.
/FTId=VAR_004433.
VARIANT 29 29 A -> S (in HNPCC2; unknown pathological
significance; acts functionally like the
wild-type protein; dbSNP:rs63750656).
{ECO:0000269|PubMed:12658575,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_043386.
VARIANT 31 31 A -> C (in HNPCC2; requires 2 nucleotide
substitutions; decreased mismatch repair
activity; dbSNP:rs63749994).
{ECO:0000269|PubMed:20020535}.
/FTId=VAR_076338.
VARIANT 32 32 I -> V (in dbSNP:rs2020872).
{ECO:0000269|Ref.5}.
/FTId=VAR_014876.
VARIANT 35 35 M -> K (in HNPCC2; unknown pathological
significance).
{ECO:0000269|PubMed:16451135}.
/FTId=VAR_043387.
VARIANT 35 35 M -> N (in MMRCS; requires 2 nucleotide
substitutions; dbSNP:rs121912965).
{ECO:0000269|PubMed:12373605,
ECO:0000269|PubMed:17440981}.
/FTId=VAR_043388.
VARIANT 35 35 M -> R (in HNPCC2; dbSNP:rs63749906).
/FTId=VAR_004434.
VARIANT 37 37 E -> ELNH (found in an endometrial cancer
sample; somatic mutation).
/FTId=VAR_004435.
VARIANT 37 37 E -> K (in HNPCC2; decreased mismatch
repair activity; loss of nuclear
localization; dbSNP:rs63751012).
{ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_076339.
VARIANT 38 38 N -> H (in HNPCC2; decreased mismatch
repair activity; no effect on nuclear
localization; dbSNP:rs63750580).
{ECO:0000269|PubMed:12373605,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_043389.
VARIANT 38 38 N -> K (in HNPCC2; decreased mismatch
repair activity; no effect on nuclear
localization; dbSNP:rs267607706).
{ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_076340.
VARIANT 41 41 D -> G (in HNPCC2; dbSNP:rs63751094).
{ECO:0000269|PubMed:15365996}.
/FTId=VAR_043390.
VARIANT 41 41 D -> H (associated with HNPCC2; no effect
on MLH1 splicing; dbSNP:rs267607713).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054522.
VARIANT 44 44 S -> F (in HNPCC2; no effect on MLH1
splicing; loss of mismatch repair
activity; dbSNP:rs63751109).
{ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:22753075,
ECO:0000269|PubMed:9326924}.
/FTId=VAR_004436.
VARIANT 45 47 TSI -> CF (in HNPCC2; decreased mismatch
repair activity; loss of protein
expression; loss of nuclear
localization).
{ECO:0000269|PubMed:21120944}.
/FTId=VAR_043391.
VARIANT 54 54 G -> E (in CRC; sporadic; somatic
mutation; unknown pathological
significance; dbSNP:rs63751267).
{ECO:0000269|PubMed:9087566}.
/FTId=VAR_012902.
VARIANT 62 62 Q -> K (in HNPCC2; decreased mismatch
repair activity; dbSNP:rs63751428).
{ECO:0000269|PubMed:9311737}.
/FTId=VAR_004437.
VARIANT 63 63 D -> E (in HNPCC2; decreased mismatch
repair activity; loss of protein
expression; loss of nuclear localization;
dbSNP:rs587778955).
{ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_043392.
VARIANT 64 64 N -> S (in HNPCC2; dbSNP:rs63750952).
{ECO:0000269|PubMed:9311737}.
/FTId=VAR_004438.
VARIANT 67 67 G -> E (in CRC; dbSNP:rs63749939).
{ECO:0000269|PubMed:18033691}.
/FTId=VAR_038024.
VARIANT 67 67 G -> R (in HNPCC2; no effect on MLH1
splicing; decreased mismatch repair
activity; loss of protein expression;
loss of nuclear localization;
dbSNP:rs63750206).
{ECO:0000269|PubMed:10375096,
ECO:0000269|PubMed:12658575,
ECO:0000269|PubMed:14961575,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:16451135,
ECO:0000269|PubMed:18561205,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075,
ECO:0000269|PubMed:9067757,
ECO:0000269|PubMed:9833759}.
/FTId=VAR_004439.
VARIANT 67 67 G -> W (in HNPCC2; dbSNP:rs63750206).
{ECO:0000269|PubMed:10480359,
ECO:0000269|PubMed:9927034}.
/FTId=VAR_012903.
VARIANT 68 68 I -> N (in HNPCC2; decreased mismatch
repair activity; dbSNP:rs63750281).
{ECO:0000269|PubMed:14961575}.
/FTId=VAR_004440.
VARIANT 69 69 R -> K (in HNPCC2; decreased mismatch
repair activity; dbSNP:rs63751661).
{ECO:0000269|PubMed:10627141}.
/FTId=VAR_004441.
VARIANT 71 71 Missing (in HNPCC2; decreased mismatch
repair activity; loss of protein
expression).
{ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_043393.
VARIANT 77 77 C -> R (in HNPCC2; decreased mismatch
repair activity; loss of nuclear
localization; normal interaction with
PMS2; dbSNP:rs63749859).
{ECO:0000269|PubMed:10660333,
ECO:0000269|PubMed:11793442,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:18561205,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_004442.
VARIANT 77 77 C -> Y (in CRC; sporadic; early onset;
dbSNP:rs63750437).
{ECO:0000269|PubMed:9032648}.
/FTId=VAR_012904.
VARIANT 80 80 F -> V (in HNPCC2; decreased mismatch
repair activity; dbSNP:rs63749990).
{ECO:0000269|PubMed:11726306,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_012905.
VARIANT 84 84 K -> E (in HNPCC2; decreased mismatch
repair activity; dbSNP:rs63750641).
{ECO:0000269|PubMed:10323887,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_012906.
VARIANT 93 93 S -> G (common polymorphism; normal
interaction with PMS2; no decrease in
mismatch repair activity; no effect on
nuclear localization; dbSNP:rs41295282).
{ECO:0000269|PubMed:10671064,
ECO:0000269|PubMed:11793442,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:18033691,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_004443.
VARIANT 98 98 G -> S (associated with HNPCC2; no effect
on MLH1 splicing; dbSNP:rs267607725).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054523.
VARIANT 101 101 G -> D (in HNPCC2; no effect on MLH1
splicing; dbSNP:rs267607727).
{ECO:0000269|PubMed:14635101,
ECO:0000269|PubMed:18561205}.
/FTId=VAR_022664.
VARIANT 101 101 G -> S (associated with HNPCC2; no effect
on MLH1 splicing; dbSNP:rs267607726).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054524.
VARIANT 102 102 E -> K (in HNPCC2; unknown pathological
significance; dbSNP:rs63750453).
{ECO:0000269|PubMed:17510385}.
/FTId=VAR_043394.
VARIANT 106 106 S -> R (in gastric cancer; unknown
pathological significance;
dbSNP:rs63750297).
{ECO:0000269|PubMed:12132870}.
/FTId=VAR_043395.
VARIANT 107 107 I -> R (in HNPCC2; decreased mismatch
repair activity; normal interaction with
PMS2; loss of protein expression; loss of
nuclear localization; dbSNP:rs63750507).
{ECO:0000269|PubMed:11793442,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_004444.
VARIANT 109 109 H -> P (in HNPCC2; decreased mismatch
repair activity; no effect on nuclear
localization; dbSNP:rs587779004).
{ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_076341.
VARIANT 109 109 H -> Q (in gastric cancer; unknown
pathological significance;
dbSNP:rs63749803).
{ECO:0000269|PubMed:12132870}.
/FTId=VAR_043396.
VARIANT 111 111 A -> P (in HNPCC2; decreased mismatch
repair activity; dbSNP:rs587779005).
{ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_076342.
VARIANT 111 111 A -> V (in HNPCC2; unknown pathological
significance; dbSNP:rs63750539).
{ECO:0000269|PubMed:10777691,
ECO:0000269|PubMed:16451135}.
/FTId=VAR_012907.
VARIANT 116 116 T -> K (associated with HNPCC2; no effect
on MLH1 splicing; dbSNP:rs63750465).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054525.
VARIANT 117 117 T -> M (in HNPCC2; decreased mismatch
repair activity; no effect on MLH1
splicing; fails to interact with PMS2 and
EXO1; loss of nuclear localization;
dbSNP:rs63750781).
{ECO:0000269|PubMed:10480359,
ECO:0000269|PubMed:11429708,
ECO:0000269|PubMed:11781295,
ECO:0000269|PubMed:12200596,
ECO:0000269|PubMed:12362047,
ECO:0000269|PubMed:12373605,
ECO:0000269|PubMed:16451135,
ECO:0000269|PubMed:18561205,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:22753075,
ECO:0000269|PubMed:8566964}.
/FTId=VAR_004445.
VARIANT 117 117 T -> R (in HNPCC2; decreased mismatch
repair activity; dbSNP:rs63750781).
{ECO:0000269|PubMed:10375096}.
/FTId=VAR_004446.
VARIANT 126 126 Y -> N (associated with HNPCC2; no effect
on MLH1 splicing; dbSNP:rs200076893).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054526.
VARIANT 128 128 A -> P (in HNPCC2; dbSNP:rs63750866).
{ECO:0000269|PubMed:9218993}.
/FTId=VAR_012908.
VARIANT 132 132 D -> H (in CRC; sporadic; susceptibility
to; ATPase function attenuated but not
eliminated; dbSNP:rs28930073).
{ECO:0000269|PubMed:15184898}.
/FTId=VAR_022665.
VARIANT 155 155 L -> R (in HNPCC2; decreased mismatch
repair activity; loss of protein
expression; loss of nuclear localization;
dbSNP:rs63750891).
{ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_043397.
VARIANT 182 182 R -> G (in HNPCC2; incomplete;
dbSNP:rs63750211).
{ECO:0000269|PubMed:10480359,
ECO:0000269|PubMed:9399661}.
/FTId=VAR_012909.
VARIANT 182 182 R -> K (in HNPCC2; dbSNP:rs587779021).
{ECO:0000269|PubMed:14635101}.
/FTId=VAR_022666.
VARIANT 185 185 V -> G (in HNPCC2; decreased mismatch
repair activity; loss of protein
expression; loss of nuclear localization;
no effect on MLH1 splicing;
dbSNP:rs63750515).
{ECO:0000269|PubMed:11781295,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_004447.
VARIANT 185 185 V -> L (in HNPCC2; unknown pathological
significance; dbSNP:rs63750012).
{ECO:0000269|PubMed:12658575}.
/FTId=VAR_043398.
VARIANT 193 193 S -> P (in HNPCC2; dbSNP:rs63751021).
{ECO:0000269|PubMed:10660333}.
/FTId=VAR_004448.
VARIANT 213 213 V -> M (common polymorphism; no effect on
MLH1 splicing; dbSNP:rs2308317).
{ECO:0000269|PubMed:10713887,
ECO:0000269|PubMed:11839723,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:18561205,
ECO:0000269|PubMed:21120944,
ECO:0000269|Ref.5}.
/FTId=VAR_012910.
VARIANT 215 215 N -> S (associated with HNPCC2; no effect
on MLH1 splicing; dbSNP:rs267607775).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054527.
VARIANT 216 216 I -> S (associated with HNPCC2; no effect
on MLH1 splicing; dbSNP:rs267607776).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054528.
VARIANT 217 217 R -> C (in HNPCC2; unknown pathological
significance; no decrease in mismatch
repair activity; dbSNP:rs4986984).
{ECO:0000269|PubMed:11781295,
ECO:0000269|PubMed:15365995,
ECO:0000269|PubMed:8797773,
ECO:0000269|PubMed:9559627}.
/FTId=VAR_004449.
VARIANT 217 217 R -> G.
/FTId=VAR_020469.
VARIANT 219 219 I -> V (common polymorphism; no decrease
in mismatch repair activity; no effect on
nuclear localization; dbSNP:rs1799977).
{ECO:0000269|PubMed:10375096,
ECO:0000269|PubMed:10777691,
ECO:0000269|PubMed:11754112,
ECO:0000269|PubMed:11781295,
ECO:0000269|PubMed:12115348,
ECO:0000269|PubMed:12200596,
ECO:0000269|PubMed:12362047,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075,
ECO:0000269|PubMed:9032648,
ECO:0000269|PubMed:9067757,
ECO:0000269|PubMed:9087566,
ECO:0000269|PubMed:9218993,
ECO:0000269|PubMed:9833759,
ECO:0000269|Ref.5}.
/FTId=VAR_004450.
VARIANT 226 295 Missing (in HNPCC2).
/FTId=VAR_004452.
VARIANT 226 226 R -> L (in HNPCC2; dbSNP:rs63751711).
{ECO:0000269|PubMed:8566964}.
/FTId=VAR_004451.
VARIANT 233 233 Missing (in HNPCC2; loss of nuclear
localization).
{ECO:0000269|PubMed:22753075}.
/FTId=VAR_076343.
VARIANT 234 234 E -> G (in HNPCC2; unknown pathological
significance; dbSNP:rs63750696).
{ECO:0000269|PubMed:12132870}.
/FTId=VAR_043399.
VARIANT 244 244 G -> D (in HNPCC2; decreased mismatch
repair activity; dbSNP:rs63750303).
{ECO:0000269|PubMed:11781295,
ECO:0000269|PubMed:12658575,
ECO:0000269|PubMed:9218993}.
/FTId=VAR_012911.
VARIANT 244 244 G -> V (in CRC; sporadic; somatic
mutation; unknown pathological
significance; dbSNP:rs63750303).
{ECO:0000269|PubMed:9087566}.
/FTId=VAR_012912.
VARIANT 247 247 S -> P (in HNPCC2; decreased mismatch
repair activity; loss of protein
expression; loss of nuclear localization;
dbSNP:rs63750948).
{ECO:0000269|PubMed:12200596,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_043400.
VARIANT 260 260 L -> F (in HNPCC2; unknown pathological
significance; no effect on MLH1 splicing;
dbSNP:rs63750642).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054529.
VARIANT 260 260 L -> R (in CRC; dbSNP:rs63751283).
{ECO:0000269|PubMed:10882759}.
/FTId=VAR_043401.
VARIANT 262 262 Missing (in HNPCC2).
{ECO:0000269|PubMed:9833759}.
/FTId=VAR_012913.
VARIANT 264 264 H -> Y (in HNPCC2; dbSNP:rs63751597).
{ECO:0000269|PubMed:10413423}.
/FTId=VAR_043402.
VARIANT 265 265 R -> C (in HNPCC2; results in partial
MLH1 exon 10 skipping on ex vivo splicing
assay; decreased mismatch repair
activity; no effect on nuclear
localization; dbSNP:rs63751194).
{ECO:0000269|PubMed:18561205,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_054530.
VARIANT 265 265 R -> H (rare polymorphism; associated
with HNPCC2; results in partial MLH1 exon
10 skipping on ex vivo splicing assay;
decreased mismatch repair activity;
dbSNP:rs63751448).
{ECO:0000269|PubMed:10573010,
ECO:0000269|PubMed:11781295,
ECO:0000269|PubMed:18561205,
ECO:0000269|PubMed:8993976}.
/FTId=VAR_012914.
VARIANT 265 265 R -> S (in HNPCC2; decreased mismatch
repair activity; dbSNP:rs63751194).
{ECO:0000269|PubMed:20020535}.
/FTId=VAR_076344.
VARIANT 268 268 E -> G (in CRC; dbSNP:rs63750650).
{ECO:0000269|PubMed:9611074}.
/FTId=VAR_012915.
VARIANT 282 282 A -> G (in HNPCC2; dbSNP:rs63750360).
{ECO:0000269|PubMed:15365995}.
/FTId=VAR_043403.
VARIANT 292 292 L -> P (in HNPCC2; unknown pathological
significance; dbSNP:rs63750517).
{ECO:0000269|PubMed:12362047,
ECO:0000269|PubMed:16451135}.
/FTId=VAR_043404.
VARIANT 295 295 S -> T (in HNPCC2; dbSNP:rs63750144).
{ECO:0000269|PubMed:9399661}.
/FTId=VAR_012916.
VARIANT 304 304 D -> V (in HNPCC2; dbSNP:rs63750993).
{ECO:0000269|PubMed:10882759}.
/FTId=VAR_043405.
VARIANT 309 309 P -> S (in dbSNP:rs267607808).
{ECO:0000269|PubMed:18033691}.
/FTId=VAR_038025.
VARIANT 320 320 E -> D (associated with HNPCC2; no effect
on MLH1 splicing; dbSNP:rs267607811).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054531.
VARIANT 321 321 S -> I (in HNPCC2; unknown pathological
significance; dbSNP:rs63750286).
{ECO:0000269|PubMed:12132870}.
/FTId=VAR_043406.
VARIANT 325 327 Missing (in CRC).
{ECO:0000269|PubMed:14504054}.
/FTId=VAR_043407.
VARIANT 325 325 R -> Q (in CRC; sporadic; somatic
mutation; unknown pathological
significance; dbSNP:rs63750268).
{ECO:0000269|PubMed:9087566}.
/FTId=VAR_012917.
VARIANT 326 326 V -> A (in HNPCC2; no decrease in
mismatch repair activity;
dbSNP:rs63751049).
{ECO:0000269|PubMed:10573010,
ECO:0000269|PubMed:11781295,
ECO:0000269|PubMed:18561205}.
/FTId=VAR_004453.
VARIANT 329 329 H -> P (in HNPCC2; loss of protein
expression; loss of nuclear localization;
dbSNP:rs63750710).
{ECO:0000269|PubMed:10323887,
ECO:0000269|PubMed:11726306,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:9272156}.
/FTId=VAR_012918.
VARIANT 330 330 Missing (in HNPCC2; results in weak MLH1
exon 11 skipping on ex vivo splicing
assay; decreased mismatch repair
activity; loss of protein expression;
loss of nuclear localization).
{ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:18561205,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_043408.
VARIANT 338 338 N -> S (in HNPCC2; dbSNP:rs63751467).
{ECO:0000269|PubMed:12095971}.
/FTId=VAR_043409.
VARIANT 379 379 Y -> C (in HNPCC2; dbSNP:rs143009528).
{ECO:0000269|PubMed:14635101}.
/FTId=VAR_022667.
VARIANT 384 384 V -> D (can be associated with HNPCC in
some populations; dbSNP:rs63750447).
{ECO:0000269|PubMed:10777691,
ECO:0000269|PubMed:8609062,
ECO:0000269|PubMed:9526167}.
/FTId=VAR_004454.
VARIANT 385 385 R -> C (in HNPCC2; unknown pathological
significance; dbSNP:rs63750760).
{ECO:0000269|PubMed:11839723}.
/FTId=VAR_043410.
VARIANT 385 385 R -> P (in HNPCC2; unknown pathological
significance; dbSNP:rs63750430).
{ECO:0000269|PubMed:10573010}.
/FTId=VAR_043411.
VARIANT 389 389 R -> W (in HNPCC2; unknown pathological
significance; no effect on nuclear
localization; normal interaction with
PMS2 and EXO1; dbSNP:rs61751644).
{ECO:0000269|PubMed:22753075}.
/FTId=VAR_076345.
VARIANT 403 403 P -> S (common polymorphism; no decrease
in mismatch repair activity; no effect on
nuclear localization; dbSNP:rs587778897).
{ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_076346.
VARIANT 406 406 S -> N (common polymorphism; no decrease
in mismatch repair activity; no effect on
nuclear localization; dbSNP:rs41294980).
{ECO:0000269|PubMed:10573010,
ECO:0000269|PubMed:18033691,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:22753075,
ECO:0000269|PubMed:9087566}.
/FTId=VAR_012919.
VARIANT 441 441 A -> T (in HNPCC2; dbSNP:rs63750365).
{ECO:0000269|PubMed:16451135,
ECO:0000269|PubMed:9326924}.
/FTId=VAR_012920.
VARIANT 443 443 K -> Q (in HNPCC2; unknown pathological
significance; no decrease in mismatch
repair activity; no effect on nuclear
localization; dbSNP:rs34213726).
{ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_043412.
VARIANT 460 460 E -> A (in HNPCC2; unknown pathological
significance; dbSNP:rs202038499).
{ECO:0000269|PubMed:21120944}.
/FTId=VAR_076347.
VARIANT 472 472 R -> I (in CRC; unknown pathological
significance; dbSNP:rs63750498).
{ECO:0000269|PubMed:12132870}.
/FTId=VAR_043413.
VARIANT 474 474 R -> Q (in HNPCC2; unknown pathological
significance; dbSNP:rs63751083).
{ECO:0000269|PubMed:17510385,
ECO:0000269|PubMed:18561205}.
/FTId=VAR_043414.
VARIANT 474 474 R -> W (associated with HNPCC2; no effect
on MLH1 splicing; dbSNP:rs147939838).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054532.
VARIANT 485 485 D -> E (in HNPCC2; dbSNP:rs63750956).
{ECO:0000269|PubMed:10375096}.
/FTId=VAR_043415.
VARIANT 485 485 D -> H (in HNPCC2; unknown pathological
significance; dbSNP:rs63750314).
{ECO:0000269|PubMed:12132870}.
/FTId=VAR_043416.
VARIANT 492 492 A -> T (in HNPCC2; also found in sporadic
colorectal cancer; dbSNP:rs63751145).
{ECO:0000269|PubMed:8872463}.
/FTId=VAR_004455.
VARIANT 506 506 V -> A (in HNPCC2; dbSNP:rs63749909).
/FTId=VAR_004456.
VARIANT 539 539 A -> D (associated with HNPCC2; no effect
on MLH1 splicing; dbSNP:rs267607843).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054533.
VARIANT 542 542 Q -> L (in HNPCC2; type II; decreased
mismatch repair activity;
dbSNP:rs63750511).
{ECO:0000269|PubMed:15365995,
ECO:0000269|PubMed:7757073,
ECO:0000269|PubMed:8797773}.
/FTId=VAR_004457.
VARIANT 542 542 Q -> P (in HNPCC2; dbSNP:rs63750511).
{ECO:0000269|PubMed:15365995}.
/FTId=VAR_043417.
VARIANT 549 549 L -> P (in HNPCC2; no effect on MLH1
splicing; dbSNP:rs63750289).
{ECO:0000269|PubMed:15365995,
ECO:0000269|PubMed:18561205,
ECO:0000269|PubMed:8797773}.
/FTId=VAR_012921.
VARIANT 550 550 L -> P (in HNPCC2; decreased mismatch
repair activity; defective in interaction
with PMS2 and EXO1; loss of protein
expression; may lose nuclear
localization; dbSNP:rs63750193).
{ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_043418.
VARIANT 551 551 N -> T (in HNPCC2; no effect on MLH1
splicing; dbSNP:rs63750271).
{ECO:0000269|PubMed:18561205,
ECO:0000269|PubMed:9399661,
ECO:0000269|PubMed:9833759}.
/FTId=VAR_012922.
VARIANT 559 559 L -> R (in HNPCC2; dbSNP:rs63750059).
{ECO:0000269|PubMed:14635101}.
/FTId=VAR_022668.
VARIANT 565 565 I -> F (in HNPCC2; dbSNP:rs63750062).
{ECO:0000269|PubMed:9833759}.
/FTId=VAR_012923.
VARIANT 574 574 L -> P (in HNPCC2; type I; abrogates
interaction with EXO1; dbSNP:rs63751608).
{ECO:0000269|PubMed:11427529,
ECO:0000269|PubMed:15365995,
ECO:0000269|PubMed:7757073,
ECO:0000269|PubMed:8797773}.
/FTId=VAR_004458.
VARIANT 578 632 Missing (in HNPCC2; decreased mismatch
repair activity; defective in interaction
with PMS2).
{ECO:0000269|PubMed:21120944}.
/FTId=VAR_076348.
VARIANT 578 578 E -> G (in HNPCC2 and CRC; unknown
pathological significance; no decrease in
mismatch repair activity; no effect on
nuclear localization; dbSNP:rs63751612).
{ECO:0000269|PubMed:10598809,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_004459.
VARIANT 582 582 L -> F (in HNPCC2; decreased mismatch
repair activity; no effect on nuclear
localization; dbSNP:rs63751713).
{ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_076349.
VARIANT 582 582 L -> V (in HNPCC2; type II;
dbSNP:rs63751713).
{ECO:0000269|PubMed:7757073}.
/FTId=VAR_004460.
VARIANT 585 585 L -> R (associated with HNPCC2; no effect
on MLH1 splicing; dbSNP:rs267607865).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054534.
VARIANT 586 586 A -> P (in HNPCC2; dbSNP:rs63751176).
{ECO:0000269|PubMed:12655562}.
/FTId=VAR_015689.
VARIANT 588 588 L -> P (in HNPCC2; dbSNP:rs63750575).
{ECO:0000269|PubMed:10777691}.
/FTId=VAR_012924.
VARIANT 589 589 A -> D (in HNPCC2; decreased mismatch
repair activity; loss of interaction with
PMS2 and EXO1; loss of protein
expression; may lose nuclear
localization; dbSNP:rs63750016).
{ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_043419.
VARIANT 596 596 Missing (in HNPCC2).
/FTId=VAR_043420.
VARIANT 601 601 D -> G (in CRC; unknown pathological
significance; dbSNP:rs63750718).
{ECO:0000269|PubMed:12655564}.
/FTId=VAR_043421.
VARIANT 603 603 P -> R (in HNPCC2; unknown pathological
significance; no effect on MLH1 splicing;
dbSNP:rs35831931).
{ECO:0000269|PubMed:11726306,
ECO:0000269|PubMed:12095971,
ECO:0000269|PubMed:18561205}.
/FTId=VAR_012925.
VARIANT 607 607 L -> H (in HNPCC2; unknown pathological
significance; also found in lobular
carcinoma in situ of the breast; no
effect on MLH1 splicing;
dbSNP:rs41295284).
{ECO:0000269|PubMed:10713887,
ECO:0000269|PubMed:11369138,
ECO:0000269|PubMed:11839723,
ECO:0000269|PubMed:18033691,
ECO:0000269|PubMed:18561205}.
/FTId=VAR_012926.
VARIANT 612 612 Missing (in HNPCC2; loss of protein
expression; loss of nuclear
localization).
{ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_043422.
VARIANT 616 616 Missing (in HNPCC2 and MMRCS; abrogates
interaction with EXO1; loss of protein
expression; loss of nuclear localization;
no effect on MLH1 splicing).
{ECO:0000269|PubMed:10480359,
ECO:0000269|PubMed:11427529,
ECO:0000269|PubMed:14635101,
ECO:0000269|PubMed:14961575,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:7661930,
ECO:0000269|PubMed:8571956,
ECO:0000269|PubMed:8872463,
ECO:0000269|PubMed:8993976,
ECO:0000269|PubMed:9311737}.
/FTId=VAR_004461.
VARIANT 618 618 K -> A (in HNPCC2; unknown pathological
significance; requires 2 nucleotide
substitutions; interacts weakly with
PMS2; no decrease in mismatch repair
activity; no effect on nuclear
localization; dbSNP:rs35502531).
{ECO:0000269|PubMed:10598809,
ECO:0000269|PubMed:10713887,
ECO:0000269|PubMed:11726306,
ECO:0000269|PubMed:11870161,
ECO:0000269|PubMed:12200596,
ECO:0000269|PubMed:12373605,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:18033691,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075,
ECO:0000269|PubMed:9311737}.
/FTId=VAR_004462.
VARIANT 618 618 K -> R (in CRC; dbSNP:rs63750449).
{ECO:0000269|PubMed:14504054}.
/FTId=VAR_043424.
VARIANT 618 618 K -> T (in HNPCC2; type II; loss of
nuclear localization; dbSNP:rs63750449).
{ECO:0000269|PubMed:10573010,
ECO:0000269|PubMed:11839723,
ECO:0000269|PubMed:12095971,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:7757073,
ECO:0000269|PubMed:8872463}.
/FTId=VAR_004463.
VARIANT 618 618 Missing (in HNPCC2).
{ECO:0000269|PubMed:16451135}.
/FTId=VAR_043423.
VARIANT 619 619 A -> P (associated with HNPCC2; no effect
on MLH1 splicing; dbSNP:rs267607866).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054535.
VARIANT 622 622 L -> H (in HNPCC2; dbSNP:rs63750693).
{ECO:0000269|PubMed:11748856}.
/FTId=VAR_012927.
VARIANT 623 623 A -> P (in HNPCC2; unknown pathological
significance).
{ECO:0000269|PubMed:16451135}.
/FTId=VAR_043425.
VARIANT 626 627 FS -> ST (in HNPCC2).
/FTId=VAR_004464.
VARIANT 631 631 D -> A (in HNPCC2; unknown pathological
significance; dbSNP:rs63750240).
{ECO:0000269|PubMed:12132870}.
/FTId=VAR_043426.
VARIANT 633 663 Missing (in HNPCC2; decreased mismatch
repair activity; defective in interaction
with PMS2; loss of protein expression;
loss of nuclear localization).
{ECO:0000269|PubMed:21120944}.
/FTId=VAR_076350.
VARIANT 635 635 N -> K (in gastric cancer; unknown
pathological significance;
dbSNP:rs63751047).
{ECO:0000269|PubMed:12132870}.
/FTId=VAR_043427.
VARIANT 636 636 L -> P (in HNPCC2; dbSNP:rs63750825).
{ECO:0000269|PubMed:15365995}.
/FTId=VAR_043428.
VARIANT 640 640 P -> L (associated with HNPCC2; no effect
on MLH1 splicing; dbSNP:rs267607875).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054536.
VARIANT 640 640 P -> S (in HNPCC2; no effect on MLH1
splicing; dbSNP:rs63749792).
{ECO:0000269|PubMed:15365995,
ECO:0000269|PubMed:18561205}.
/FTId=VAR_043429.
VARIANT 646 646 Y -> C (in HNPCC2; defective in
interaction with PMS2 and EXO1; no
decrease in mismatch repair activity;
dbSNP:rs35045067).
{ECO:0000269|PubMed:11870161,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_043430.
VARIANT 648 648 P -> L (in HNPCC2; unknown pathological
significance; defective in interaction
with PMS2 and EXO1; may lose nuclear
localization; loss of protein expression;
no decrease in mismatch repair activity;
dbSNP:rs63750610).
{ECO:0000269|PubMed:11726306,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_012928.
VARIANT 648 648 P -> S (in HNPCC2; the protein is
unstable; loss of nuclear localization;
loss of protein expression; no decrease
in mismatch repair activity;
dbSNP:rs63750899).
{ECO:0000269|PubMed:11839723,
ECO:0000269|PubMed:15139004,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_022669.
VARIANT 654 654 P -> L (in HNPCC2; decreased mismatch
repair activity; defective in interaction
with PMS2 and EXO1; loss of protein
expression; may lose nuclear
localization; dbSNP:rs63750726).
{ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075}.
/FTId=VAR_043431.
VARIANT 655 655 I -> V (in HNPCC2; also found in an
endometrial cancer sample; no effect on
MLH1 splicing; dbSNP:rs55907433).
{ECO:0000269|PubMed:12115348,
ECO:0000269|PubMed:18561205}.
/FTId=VAR_043432.
VARIANT 656 656 F -> S (in HNPCC2; no effect on MLH1
splicing; dbSNP:rs267607876).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054537.
VARIANT 657 657 Missing (in HNPCC2; unknown pathological
significance).
{ECO:0000269|PubMed:16451135}.
/FTId=VAR_043433.
VARIANT 659 659 R -> L (in HNPCC2; dbSNP:rs63749900).
{ECO:0000269|PubMed:10713887,
ECO:0000269|PubMed:11427529}.
/FTId=VAR_012929.
VARIANT 659 659 R -> P (in HNPCC2; interacts only very
weakly with PMS2; abrogates interaction
with EXO1; decreased mismatch repair
activity; may lose nuclear localization;
dbSNP:rs63749900).
{ECO:0000269|PubMed:11793442,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075,
ECO:0000269|PubMed:9311737}.
/FTId=VAR_004465.
VARIANT 659 659 R -> Q (in HNPCC2; unknown pathological
significance; dbSNP:rs63749900).
{ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_043434.
VARIANT 662 662 T -> P (in HNPCC2; unknown pathological
significance; dbSNP:rs587778964).
{ECO:0000269|PubMed:11726306,
ECO:0000269|PubMed:11754112}.
/FTId=VAR_012930.
VARIANT 666 666 W -> R (in HNPCC2; unknown pathological
significance; no effect on MLH1 splicing;
dbSNP:rs267607887).
{ECO:0000269|PubMed:18561205}.
/FTId=VAR_054538.
VARIANT 681 681 A -> T (in HNPCC2 and CRC; abrogates
interaction with EXO1; no decrease in
mismatch repair activity;
dbSNP:rs63750217).
{ECO:0000269|PubMed:11427529,
ECO:0000269|PubMed:12362047,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:16451135,
ECO:0000269|PubMed:18033691,
ECO:0000269|PubMed:18561205,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_004466.
VARIANT 687 687 R -> W (in HNPCC2; unknown pathological
significance; dbSNP:rs63751275).
{ECO:0000269|PubMed:11748856,
ECO:0000269|PubMed:12362047,
ECO:0000269|PubMed:16451135,
ECO:0000269|PubMed:21120944}.
/FTId=VAR_012931.
VARIANT 689 689 Q -> R (in HNPCC; unknown pathological
significance; dbSNP:rs63750702).
{ECO:0000269|PubMed:11726306,
ECO:0000269|PubMed:18033691,
ECO:0000269|PubMed:18561205}.
/FTId=VAR_012932.
VARIANT 716 716 V -> M (common polymorphism; no decrease
in mismatch repair activity; no effect on
nuclear localization; dbSNP:rs35831931).
{ECO:0000269|PubMed:10573010,
ECO:0000269|PubMed:11726306,
ECO:0000269|PubMed:12200596,
ECO:0000269|PubMed:16083711,
ECO:0000269|PubMed:18033691,
ECO:0000269|PubMed:20020535,
ECO:0000269|PubMed:21120944,
ECO:0000269|PubMed:22753075,
ECO:0000269|PubMed:9833759}.
/FTId=VAR_012933.
VARIANT 718 718 H -> Y (in HNPCC2; unknown pathological
significance; dbSNP:rs2020873).
{ECO:0000269|PubMed:10386556,
ECO:0000269|PubMed:12095971,
ECO:0000269|PubMed:18033691}.
/FTId=VAR_004467.
VARIANT 719 719 I -> INVFHI (in HNPCC2).
/FTId=VAR_043435.
VARIANT 724 724 L -> M (in HNPCC2; dbSNP:rs63749875).
{ECO:0000269|PubMed:15365995}.
/FTId=VAR_043436.
VARIANT 729 729 L -> V (in dbSNP:rs1800149).
/FTId=VAR_004468.
VARIANT 749 749 L -> P (in CRC; dbSNP:rs267607894).
{ECO:0000269|PubMed:14504054}.
/FTId=VAR_043437.
VARIANT 751 751 K -> R (in HNPCC2; unknown pathological
significance; dbSNP:rs140195825).
{ECO:0000269|PubMed:11139242,
ECO:0000269|PubMed:16451135,
ECO:0000269|PubMed:18033691}.
/FTId=VAR_012934.
VARIANT 755 755 R -> W (in HNPCC; incomplete;
dbSNP:rs267607900).
{ECO:0000269|PubMed:10480359}.
/FTId=VAR_012935.
CONFLICT 352 352 L -> H (in Ref. 6; BAG60773).
{ECO:0000305}.
CONFLICT 708 711 Missing (in Ref. 4; AAA85687).
{ECO:0000305}.
HELIX 13 25 {ECO:0000244|PDB:4P7A}.
HELIX 28 41 {ECO:0000244|PDB:4P7A}.
STRAND 45 52 {ECO:0000244|PDB:4P7A}.
TURN 53 56 {ECO:0000244|PDB:4P7A}.
STRAND 57 63 {ECO:0000244|PDB:4P7A}.
HELIX 70 72 {ECO:0000244|PDB:4P7A}.
TURN 73 77 {ECO:0000244|PDB:4P7A}.
HELIX 103 109 {ECO:0000244|PDB:4P7A}.
STRAND 110 118 {ECO:0000244|PDB:4P7A}.
STRAND 122 131 {ECO:0000244|PDB:4P7A}.
STRAND 134 137 {ECO:0000244|PDB:4P7A}.
STRAND 140 142 {ECO:0000244|PDB:4P7A}.
STRAND 146 154 {ECO:0000244|PDB:4P7A}.
TURN 155 158 {ECO:0000244|PDB:4P7A}.
HELIX 160 165 {ECO:0000244|PDB:4P7A}.
HELIX 169 186 {ECO:0000244|PDB:4P7A}.
TURN 187 189 {ECO:0000244|PDB:4P7A}.
STRAND 190 196 {ECO:0000244|PDB:4P7A}.
STRAND 203 205 {ECO:0000244|PDB:4P7A}.
HELIX 212 220 {ECO:0000244|PDB:4P7A}.
HELIX 222 225 {ECO:0000244|PDB:4P7A}.
STRAND 228 235 {ECO:0000244|PDB:4P7A}.
TURN 236 239 {ECO:0000244|PDB:4P7A}.
STRAND 240 247 {ECO:0000244|PDB:4P7A}.
STRAND 253 255 {ECO:0000244|PDB:4P7A}.
STRAND 257 262 {ECO:0000244|PDB:4P7A}.
HELIX 270 281 {ECO:0000244|PDB:4P7A}.
STRAND 291 298 {ECO:0000244|PDB:4P7A}.
HELIX 322 335 {ECO:0000244|PDB:4P7A}.
HELIX 504 516 {ECO:0000244|PDB:3RBN}.
HELIX 519 526 {ECO:0000244|PDB:3RBN}.
STRAND 529 543 {ECO:0000244|PDB:3RBN}.
STRAND 546 551 {ECO:0000244|PDB:3RBN}.
HELIX 552 566 {ECO:0000244|PDB:3RBN}.
STRAND 572 581 {ECO:0000244|PDB:3RBN}.
HELIX 582 590 {ECO:0000244|PDB:3RBN}.
HELIX 593 595 {ECO:0000244|PDB:3RBN}.
HELIX 604 626 {ECO:0000244|PDB:3RBN}.
STRAND 634 641 {ECO:0000244|PDB:3RBN}.
HELIX 650 652 {ECO:0000244|PDB:3RBN}.
HELIX 653 662 {ECO:0000244|PDB:3RBN}.
HELIX 669 684 {ECO:0000244|PDB:3RBN}.
HELIX 688 690 {ECO:0000244|PDB:3RBN}.
HELIX 712 718 {ECO:0000244|PDB:3RBN}.
HELIX 720 724 {ECO:0000244|PDB:3RBN}.
HELIX 732 735 {ECO:0000244|PDB:3RBN}.
STRAND 737 745 {ECO:0000244|PDB:3RBN}.
SEQUENCE 756 AA; 84601 MW; C9231FC406C2CA20 CRC64;
MSFVAGVIRR LDETVVNRIA AGEVIQRPAN AIKEMIENCL DAKSTSIQVI VKEGGLKLIQ
IQDNGTGIRK EDLDIVCERF TTSKLQSFED LASISTYGFR GEALASISHV AHVTITTKTA
DGKCAYRASY SDGKLKAPPK PCAGNQGTQI TVEDLFYNIA TRRKALKNPS EEYGKILEVV
GRYSVHNAGI SFSVKKQGET VADVRTLPNA STVDNIRSIF GNAVSRELIE IGCEDKTLAF
KMNGYISNAN YSVKKCIFLL FINHRLVEST SLRKAIETVY AAYLPKNTHP FLYLSLEISP
QNVDVNVHPT KHEVHFLHEE SILERVQQHI ESKLLGSNSS RMYFTQTLLP GLAGPSGEMV
KSTTSLTSSS TSGSSDKVYA HQMVRTDSRE QKLDAFLQPL SKPLSSQPQA IVTEDKTDIS
SGRARQQDEE MLELPAPAEV AAKNQSLEGD TTKGTSEMSE KRGPTSSNPR KRHREDSDVE
MVEDDSRKEM TAACTPRRRI INLTSVLSLQ EEINEQGHEV LREMLHNHSF VGCVNPQWAL
AQHQTKLYLL NTTKLSEELF YQILIYDFAN FGVLRLSEPA PLFDLAMLAL DSPESGWTEE
DGPKEGLAEY IVEFLKKKAE MLADYFSLEI DEEGNLIGLP LLIDNYVPPL EGLPIFILRL
ATEVNWDEEK ECFESLSKEC AMFYSIRKQY ISEESTLSGQ QSEVPGSIPN SWKWTVEHIV
YKALRSHILP PKHFTEDGNI LQLANLPDLY KVFERC


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