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UniProtKB/Swiss-Prot P40692: Variant p.Ala681Thr

DNA mismatch repair protein Mlh1
Gene: MLH1
Chromosomal location: 3p21.3
Variant information

Variant position:  681
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Alanine (A) to Threonine (T) at position 681 (A681T, p.Ala681Thr).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from small size and hydrophobic (A) to medium size and polar (T)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  0
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in 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.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Involvement in 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.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In HNPCC2 and CRC; abrogates interaction with EXO1; no decrease in mismatch repair activity.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  681
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  756
The length of the canonical sequence.

Location on the sequence:   ATEVNWDEEKECFESLSKEC  A MFYSIRKQYISEESTLSGQQ
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         ATEV-NWDEEKECFESLSKECAMFYSIRK-QYI-SEESTLSGQQ

Mouse                         ATEV-NWDEEKECFESLSKECAMFYSIRK-QYI-LEESTLS

Rat                           ATEV-NW-DEEECFESLSKECAVFYSIRK-QYI-LEESALS

Slime mold                    ATEV-EWEFEKECFAGIVKEISSFFKIEP-SFLKLRDTQVN

Baker's yeast                 GKEV-DWEDEQECLDGILREIALLYIPDMVPKVDTSDASLS

Fission yeast                 TPKFFDWLDEKSCLNGIMKAIAKFYVP----------LPLS

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 2 – 756 DNA mismatch repair protein Mlh1
Helix 669 – 684


Literature citations

The interaction of DNA mismatch repair proteins with human exonuclease I.
Schmutte C.; Sadoff M.M.; Shim K.-S.; Acharya S.; Fishel R.;
J. Biol. Chem. 276:33011-33018(2001)
Cited for: INTERACTION WITH EXO1 AND PMS2; CHARACTERIZATION OF VARIANTS HNPCC2 PRO-574; LYS-616 DEL; LEU-659 AND THR-681; CHARACTERIZATION OF VARIANT MMRCS LYS-616 DEL;

Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants.
Kansikas M.; Kariola R.; Nystroem M.;
Hum. Mutat. 32:107-115(2011)
Cited for: 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; FUNCTION;

Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States.
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.;
J. Med. Genet. 39:E65-E65(2002)
Cited for: VARIANTS HNPCC2 PHE-19; LEU-28; MET-117; PRO-292; THR-681 AND TRP-687; VARIANT VAL-219;

Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1.
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.;
Gastroenterology 129:537-549(2005)
Cited for: 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; CHARACTERIZATION OF VARIANTS SER-29; GLY-93; MET-213; VAL-219; GLN-443; ALA-618; CYS-646; GLN-659; THR-681 AND MET-716;

Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study).
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.;
Clin. Genet. 69:40-47(2006)
Cited for: 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;

Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer.
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.;
Hum. Mutat. 29:367-374(2008)
Cited for: VARIANTS CRC GLU-67 AND THR-681; VARIANTS ALA-22; GLY-93; SER-309; ASN-406; HIS-607; ALA-618; ARG-689; MET-716; TYR-718 AND ARG-751;

A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects.
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.;
Hum. Mutat. 29:1412-1424(2008)
Cited for: VARIANT HNPCC2 ILE-330 DEL; 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;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.