UniProtKB/Swiss-Prot P40692: Variant p.Pro28Leu

DNA mismatch repair protein Mlh1
Gene: MLH1
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Variant information Variant position:

28 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

LP/P [Disclaimer] 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 Proline (P) to Leucine (L) at position 28 (P28L, p.Pro28Leu). 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 hydrophobic. 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 LYNCH2; loss of protein expression; normal interaction with PMS2 and EXO1; 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.

Variant rs63750792 [ dbSNP | Ensembl ]

Sequence information Variant position:

28 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:

IRRLDETVVNRIAAGEVIQR P ANAIKEMIENCLDAKSTSIQ 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                         IRRLDETVVNRIAAGEVIQRPANAIKEMIENCLDAKSTSIQ

Mouse                         IRRLDETVVNRIAAGEVIQRPANAIKEMIENCLDAKSTNIQ

Rat                           IRRLDETVVNRIAAGEVIQRPANAIKEMTENCLDAKSTNIQ

Slime mold                    IHRLTQEVVNKISAGEVIQRPSNALKELLENCLDAKSTTIT

Baker's yeast                 IKALDASVVNKIAAGEIIISPVNALKEMMENSIDANATMID

Fission yeast                 IRPLDQLVINKIAAGEIIERPENAIKELIENSLDAGSTSID

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.

Type	Positions	Description
Chain	2 – 756	DNA mismatch repair protein Mlh1
Binding site	38 – 38
Modified residue	33 – 33	N6-acetyllysine
Alternative sequence	1 – 241	Missing. In isoform 2.
Alternative sequence	1 – 101	MSFVAGVIRRLDETVVNRIAAGEVIQRPANAIKEMIENCLDAKSTSIQVIVKEGGLKLIQIQDNGTGIRKEDLDIVCERFTTSKLQSFEDLASISTYGFRG -> MAF. In isoform 3.
Mutagenesis	33 – 33	K -> Q. Abolishes acetylation; when associated with Q-241, Q-361 and Q-377.
Mutagenesis	33 – 33	K -> R. Abolishes acetylation and binding affinity for MSH6 and MSH2; when associated with R-241, R-361 and R-377.
Helix	28 – 41

Literature citations
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; Hereditary nonpolyposis colorectal cancer (HNPCC): eight novel germline mutations in hMSH2 or hMLH1 genes.
Wehner M.; Buschhausen L.; Lamberti C.; Kruse R.; Caspari R.; Propping P.; Friedl W.;
Hum. Mutat. 10:241-244(1997)
Cited for: VARIANT LYNCH2 LEU-28; 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.
Lamberti C.; Kruse R.; Ruelfs C.; Caspari R.; Wang Y.; Jungck M.; Mathiak M.; Malayeri H.R.H.; Friedl W.; Sauerbruch T.; Propping P.;
Gut 44:839-843(1999)
Cited for: VARIANTS LYNCH2 LEU-28; GLU-84 AND PRO-329; 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 LYNCH2 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 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; 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 LYNCH2 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; 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.