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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P40692: Variant p.Val716Met

DNA mismatch repair protein Mlh1
Gene: MLH1
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Variant information Variant position: help 716 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: help LB/B 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: help From Valine (V) to Methionine (M) at position 716 (V716M, p.Val716Met). 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: help Similar physico-chemical property. Both residues are medium size and hydrophobic. The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help 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

Variant description: help No decrease in mismatch repair activity; no effect on nuclear localization. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 716 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 756 The length of the canonical sequence.
Location on the sequence: help TLSGQQSEVPGSIPNSWKWT V EHIVYKALRSHILPPKHFTE 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: help The multiple alignment of the region surrounding the variant against various orthologous sequences.
Human                         TLSGQQSEVPGSIPNSW--------KWTVEHIVYKALRSHILPPKHFTE

Mouse                         TLSGQQSDMPGSTSKPW--------KWTVEHIIYKAFRSHL

Rat                           ALSGQQSDMPGSPSKPW--------KWTVEHIIYKAFRSHL

Slime mold                    QVNNQQQTNSTTTTNNINFIKKDGKEWIIQHLIFPAFR-KL

Baker's yeast                 SLSEDEKAQFINRKEHI--------SSLLEHVLFPCIKRRF

Fission yeast                 -LSYEESDVKSIRSL----------ESCLEDYLFPEFRRRV

Sequence annotation in neighborhood: help 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 712 – 718



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 LYNCH2 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; 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 LYNCH2 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; Excess of hMLH1 germline mutations in Swiss families with hereditary non-polyposis colorectal cancer.
Hutter P.; Couturier A.; Membrez V.; Joris F.; Sappino A.-P.; Chappuis P.O.;
Int. J. Cancer 78:680-684(1998)
Cited for: VARIANTS LYNCH2 ARG-67; ILE-262 DEL; THR-551 AND PHE-565; VARIANTS VAL-219 AND MET-716; Assessment of pathogenicity criteria for constitutional missense mutations of the hereditary nonpolyposis colorectal cancer genes MLH1 and MSH2.
Genuardi M.; Carrara S.; Anti M.; Ponz de Leon M.; Viel A.;
Eur. J. Hum. Genet. 7:778-782(1999)
Cited for: VARIANTS HIS-265; ALA-326; PRO-385; ASN-406; THR-618 AND MET-716; Impact of microsatellite testing and mismatch repair protein expression on the clinical interpretation of genetic testing in hereditary non-polyposis colorectal cancer.
Ward R.; Meldrum C.; Williams R.; Mokany E.; Scott R.; Turner J.; Hawkins N.; Burgess B.; Groombridge C.; Spigelman A.;
J. Cancer Res. Clin. Oncol. 128:403-411(2002)
Cited for: VARIANTS LYNCH2 MET-117 AND PRO-247; VARIANTS VAL-219; ALA-618 AND MET-716; 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 LYNCH2 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 LYNCH2 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; 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; 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 LYNCH2 CYS-233 DEL AND TRP-389; CHARACTERIZATION OF VARIANTS LYNCH2 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.