Home  |  Contact

UniProtKB/Swiss-Prot P40692: Variant p.Asn38His

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

Variant position:  38
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 Asparagine (N) to Histidine (H) at position 38 (N38H, p.Asn38His).
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:  Similar physico-chemical property. Both residues are medium size and polar.
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  1
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.

Variant description:  In HNPCC2; decreased mismatch repair activity; no effect on nuclear localization.
Any additional useful information about the variant.

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



Sequence information

Variant position:  38
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:   RIAAGEVIQRPANAIKEMIE  N CLDAKSTSIQVIVKEGGLKL
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                         RIAAGEVIQRPANAIKEMIENCLDAKSTSIQVIVKEGGLKL

Mouse                         RIAAGEVIQRPANAIKEMIENCLDAKSTNIQVVVKEGGLKL

Rat                           RIAAGEVIQRPANAIKEMTENCLDAKSTNIQVIVREGGLKL

Slime mold                    KISAGEVIQRPSNALKELLENCLDAKSTTITVTVKDGGMKF

Baker's yeast                 KIAAGEIIISPVNALKEMMENSIDANATMIDILVKEGGIKV

Fission yeast                 KIAAGEIIERPENAIKELIENSLDAGSTSIDVLLKDGGLKL

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
Binding site 38 – 38 ATP
Alternative sequence 1 – 241 Missing. In isoform 2.
Alternative sequence 1 – 101 MSFVAGVIRRLDETVVNRIAAGEVIQRPANAIKEMIENCLDAKSTSIQVIVKEGGLKLIQIQDNGTGIRKEDLDIVCERFTTSKLQSFEDLASISTYGFRG -> MAF. In isoform 3.
Helix 28 – 41


Literature citations

A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1.
Drost M.; Zonneveld J.B.; van Dijk L.; Morreau H.; Tops C.M.; Vasen H.F.; Wijnen J.T.; de Wind N.;
Hum. Mutat. 31:247-253(2010)
Cited for: 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; FUNCTION;

Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach.
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.;
Br. J. Cancer 87:892-897(2002)
Cited for: VARIANTS HNPCC2 ASN-35; HIS-38; MET-117 AND ALA-618;

Functional characterization of MLH1 missense variants identified in Lynch syndrome patients.
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.;
Hum. Mutat. 33:1647-1655(2012)
Cited for: 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; SUBCELLULAR LOCATION;

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.