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UniProtKB/Swiss-Prot P40692: Variant p.Leu607His

DNA mismatch repair protein Mlh1
Gene: MLH1
Variant information

Variant position:  607
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  US
The variants are classified into three categories: LP/P, LB/B and US.
  • LP/P: likely pathogenic or pathogenic.
  • LB/B: likely benign or benign.
  • US: uncertain significance

Residue change:  From Leucine (L) to Histidine (H) at position 607 (L607H, p.Leu607His).
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 medium size and hydrophobic (L) to medium size and polar (H)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
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

Variant description:  In HNPCC2; unknown pathological significance; also found in lobular carcinoma in situ of the breast; no effect on MLH1 splicing.
Any additional useful information about the variant.

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



Sequence information

Variant position:  607
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:   MLALDSPESGWTEEDGPKEG  L AEYIVEFLKKKAEMLADYFS
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                         MLALDSPESGWTEEDGPKEGLAEYIVEFLKKKAEMLADYFS

Mouse                         MLALDSPESGWTEDDGPKEGLAEYIVEFLKKKAEMLADYFS

Rat                           MLALDSPESGWTEEDGPKEGLAEYIVEFLKKKAKMLADYFS

Slime mold                    LVSLDSPLSGWMESDGPKDKIADYLTKLLISKKELLNEYFS

Baker's yeast                 LYNLLSEFDE-LNDDASKEK----IISKIWDMSSMLNEYYS

Fission yeast                 EIV-----NG-DEDKSESEK----FTRLLVSRRDMLKDYFS

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
Region 410 – 650 Interaction with EXO1
Helix 604 – 626


Literature citations

Detection of mutations in mismatch repair genes in Portuguese families with hereditary non-polyposis colorectal cancer (HNPCC) by a multi-method approach.
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.;
Eur. J. Hum. Genet. 8:49-53(2000)
Cited for: VARIANTS HNPCC2 HIS-607; ALA-618 AND LEU-659; VARIANT MET-213;

Contribution of germline MLH1 and MSH2 mutations to lobular carcinoma in situ of the breast.
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.;
Cancer Lett. 167:171-174(2001)
Cited for: VARIANT HIS-607;

Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1 mismatch repair genes: implications for genetic testing.
Cravo M.; Afonso A.J.; Lage P.; Albuquerque C.; Maia L.; Lacerda C.; Fidalgo P.; Chaves P.; Cruz C.; Nobre-Leitao C.;
Gut 50:405-412(2002)
Cited for: VARIANTS HNPCC2 CYS-385; HIS-607; THR-618 AND SER-648; VARIANT MET-213;

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.