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UniProtKB/Swiss-Prot P43246: Variant p.Ala272Val

DNA mismatch repair protein Msh2
Gene: MSH2
Variant information

Variant position:  272
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Unclassified
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 Valine (V) at position 272 (A272V, p.Ala272Val).
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 hydrophobic (V)
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 1 (HNPCC1) [MIM:120435]: 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:10375096, ECO:0000269|PubMed:10386556, ECO:0000269|PubMed:10528862, ECO:0000269|PubMed:10573010, ECO:0000269|PubMed:10612836, ECO:0000269|PubMed:10777691, ECO:0000269|PubMed:10829038, ECO:0000269|PubMed:11726306, ECO:0000269|PubMed:11870161, ECO:0000269|PubMed:11920458, ECO:0000269|PubMed:12112654, ECO:0000269|PubMed:12124176, ECO:0000269|PubMed:12132870, ECO:0000269|PubMed:12200596, ECO:0000269|PubMed:12362047, ECO:0000269|PubMed:12373605, ECO:0000269|PubMed:12655564, ECO:0000269|PubMed:12655568, ECO:0000269|PubMed:12658575, ECO:0000269|PubMed:14635101, ECO:0000269|PubMed:15046096, ECO:0000269|PubMed:15300854, ECO:0000269|PubMed:15342696, ECO:0000269|PubMed:15365995, ECO:0000269|PubMed:15613555, ECO:0000269|PubMed:15870828, ECO:0000269|PubMed:15896463, ECO:0000269|PubMed:15991316, ECO:0000269|PubMed:15996210, ECO:0000269|PubMed:16451135, ECO:0000269|PubMed:17101317, ECO:0000269|PubMed:17128465, ECO:0000269|PubMed:18561205, ECO:0000269|PubMed:18625694, ECO:0000269|PubMed:18781619, ECO:0000269|PubMed:18822302, ECO:0000269|PubMed:18951462, ECO:0000269|PubMed:21120944, ECO:0000269|PubMed:22102614, ECO:0000269|PubMed:22371642, ECO:0000269|PubMed:7874129, ECO:0000269|PubMed:8261515, ECO:0000269|PubMed:8700523, ECO:0000269|PubMed:8797773, ECO:0000269|PubMed:8872463, ECO:0000269|PubMed:9048925, ECO:0000269|PubMed:9240418, ECO:0000269|PubMed:9298827, ECO:0000269|PubMed:9311737, ECO:0000269|PubMed:9419403, ECO:0000269|PubMed:9559627, ECO:0000269|PubMed:9621522, ECO:0000269|PubMed:9718327, ECO:0000269|PubMed:9889267}. 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 HNPCC1; unknown pathological significance; shows slightly reduced mismatch binding or release efficiency; results in partial MSH2 exon 5 skipping; normal mismatch repair activity.
Any additional useful information about the variant.

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

Sequence information

Variant position:  272
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  934
The length of the canonical sequence.

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.


Mouse                         QINSAALPEMENQVAVSSLSAVIKFL--ELLSDD------S

Rat                           QMNSAVLPEMENQVAVSSLSAVIKFL--ELLSDD------S

Bovine                        QVNSAVLPEMENQVAVSSLSAVIKFL--ELLSDD------S

Drosophila                    QEDATGLKELQLQLASNALKTAIKYL--DLVNDA------G

Slime mold                    VKNN--LPDIEQEHAIQSASCLIKHL--DLLSNP------N

Baker's yeast                 DLALS-LPQKYSKLSMGACNALIGYL--QLLSEQ------D


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.

Chain 2 – 934 DNA mismatch repair protein Msh2
Helix 264 – 277

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 HNPCC1 PRO-33; MET-44; VAL-45; SER-127; MET-145; ASP-161; ARG-162; ARG-164; PRO-173; ARG-187; PRO-187; VAL-272; TYR-333; LEU-519; ASN-603; PRO-636; ALA-674; VAL-688; PHE-697; 745-ILE-ILE-746 DEL; LYS-749; THR-834; GLY-886 AND GLU-923; CHARACTERIZATION OF VARIANTS ASP-322 AND ILE-722; FUNCTION;

Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein.
Ollila S.; Sarantaus L.; Kariola R.; Chan P.; Hampel H.; Holinski-Feder E.; Macrae F.; Kohonen-Corish M.; Gerdes A.-M.; Peltomaeki P.; Mangold E.; de la Chapelle A.; Greenblatt M.; Nystroem M.;
Gastroenterology 131:1408-1417(2006)
Cited for: VARIANTS HNPCC1 PRO-33; ASP-161; ARG-162; ARG-164; PRO-173; PRO-187; TYR-333; ASN-603; PRO-636; PHE-697; 745-ILE-ILE-746 DEL AND LYS-749; VARIANTS VAL-272; THR-834 AND GLU-923; CHARACTERIZATION OF VARIANTS HNPCC1 PRO-33; ASP-161; ARG-162; ARG-164; PRO-173; PRO-187; TYR-333; ASN-603; PRO-636; PHE-697; 745-ILE-ILE-746 DEL AND LYS-749; CHARACTERIZATION OF VARIANTS VAL-272; THR-834 AND GLU-923;

Mechanisms of pathogenicity in human MSH2 missense mutants.
Ollila S.; Dermadi Bebek D.; Jiricny J.; Nystroem M.;
Hum. Mutat. 29:1355-1363(2008)
Cited for: CHARACTERIZATION OF VARIANTS HNPCC1 PRO-33; SER-127; ASP-161; ARG-162; ARG-164; PRO-173; PRO-187; VAL-272; TYR-333; ASN-603; PRO-636; ALA-674; PHE-697; 745-ILE-ILE-746 DEL; LYS-749; THR-834 AND GLU-923; CHARACTERIZATION OF VARIANT ASP-322;

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: VARIANTS HNPCC1 LEU-92 DEL; ARG-199; ASP-331; GLU-470; ASN-610; GLY-638; GLU-645; LEU-696; TYR-748 AND GLN-839; VARIANTS VAL-272; ASN-596 DEL; TYR-671; ARG-697 AND PHE-723; CHARACTERIZATION OF VARIANTS HNPCC1 LEU-92 DEL; ARG-199; ASP-331; GLU-470; ASN-610; GLY-638; GLU-645; LEU-696; TYR-748 AND GLN-839; CHARACTERIZATION OF VARIANTS VAL-272; ASN-596 DEL; TYR-671; ARG-697 AND PHE-723;

A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants.
Drost M.; Zonneveld J.B.; van Hees S.; Rasmussen L.J.; Hofstra R.M.; de Wind N.;
Hum. Mutat. 33:488-494(2012)
Cited for: CHARACTERIZATION OF VARIANTS HNPCC1 MET-44; VAL-45; HIS-167; THR-305; PHE-390; ASN-596 DEL; ARG-639; ARG-674; PHE-697; PHE-723 AND GLY-886; CHARACTERIZATION OF VARIANTS ASP-165; HIS-177; VAL-272; LEU-385; LEU-519; ALA-675; GLU-759; VAL-805; GLY-843 AND LEU-860;

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.