UniProtKB/Swiss-Prot P52701: Variant p.Val878Ala

DNA mismatch repair protein Msh6
Gene: MSH6
Chromosomal location: 2p16
Variant information

Variant position:  878
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 have been found in patients and disease-association is reported in literature. However, this classification is not a definitive assessment of variant pathogenicity.
  • Polymorphism: No disease-association has been reported.
  • Unclassified: Variants have been found in patients but disease-association remains unclear.

Residue change:  From Valine (V) to Alanine (A) at position 878 (V878A, p.Val878Ala).
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 (V) to small size and hydrophobic (A)
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 5 (HNPCC5) [MIM:614350]: 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:10480359, ECO:0000269|PubMed:10521294, ECO:0000269|PubMed:11586295, ECO:0000269|PubMed:12658575, ECO:0000269|PubMed:14974087, ECO:0000269|PubMed:15365995, ECO:0000269|PubMed:21120944, ECO:0000269|PubMed:9354786}. 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.

Involvement in disease:  Endometrial cancer (ENDMC) [MIM:608089]: A malignancy of endometrium, the mucous lining of the uterus. Most endometrial cancers are adenocarcinomas, cancers that begin in cells that make and release mucus and other fluids. {ECO:0000269|PubMed:11153917, ECO:0000269|PubMed:14961575}. Note=Disease susceptibility is associated with variations 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.

Involvement in disease:  Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:10413423, ECO:0000269|PubMed:10537275, ECO:0000269|PubMed:10699937, ECO:0000269|PubMed:11153917, ECO:0000269|PubMed:11470537, ECO:0000269|PubMed:11709755, ECO:0000269|PubMed:11807791, ECO:0000269|PubMed:12522549, ECO:0000269|PubMed:14520694, ECO:0000269|PubMed:15483016, ECO:0000269|PubMed:22102614}. Note=Disease susceptibility is associated with variations 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 HNPCC5, CRC and ENDMC; unknown pathological significance; 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:  878
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  1360
The length of the canonical sequence.

Location on the sequence:   FLSALEGFKVMCKIIGIMEE  V ADGFKSKILKQVISLQTKNP
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                         FLSALEGFKVMCKIIGIMEEVADGFKSKILKQVISLQTKNP

Mouse                         FLSALEGFKVMCKVSGLLEEVAGGFTSKTLKQVVTLQSKSP

Chicken                       FLSALEGFKVMNEIVDAMEEVASDFKSQVLKQLVTRKAKHP

Drosophila                    FMAVLKGFNDLTKLPTMF----HQCKTTLLKRITQLPESG-

Slime mold                    LISVLNHFDNIHSKLLELLDEAEQIESIHLRSCLFMDNQQD

Baker's yeast                 FEKVITAFETIIELQDSLK--NNDLKGDVSKYI--------

Fission yeast                 FVRVLEGFQRINSAFDQL---REEFMEVAEGTLLGEIIQSA

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 1 – 1360 DNA mismatch repair protein Msh6
Helix 847 – 879


Literature citations

Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium?
Charames G.S.; Millar A.L.; Pal T.; Narod S.; Bapat B.;
Hum. Genet. 107:623-629(2000)
Cited for: VARIANTS CRC VAL-20; ALA-878 AND HIS-901; VARIANTS ENDMC VAL-20; ALA-878 AND HIS-901;

Germline and somatic mutations in hMSH6 and hMSH3 in gastrointestinal cancers of the microsatellite mutator phenotype.
Ohmiya N.; Matsumoto S.; Yamamoto H.; Baranovskaya S.; Malkhosyan S.R.; Perucho M.;
Gene 272:301-313(2001)
Cited for: VARIANTS CRC ALA-685; GLN-772; ALA-800; MET-854; ALA-878; VAL-1031 AND ARG-1158;

A role for MLH3 in hereditary nonpolyposis colorectal cancer.
Wu Y.; Berends M.J.W.; Sijmons R.H.; Mensink R.G.J.; Verlind E.; Kooi K.A.; van der Sluis T.; Kempinga C.; van der Zee A.G.J.; Hollema H.; Buys C.H.C.M.; Kleibeuker J.H.; Hofstra R.M.W.;
Nat. Genet. 29:137-138(2001)
Cited for: VARIANT HNPCC5 ALA-878;

Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant.
Berends M.J.W.; Wu Y.; Sijmons R.H.; Mensink R.G.J.; van der Sluis T.; Hordijk-Hos J.M.; de Vries E.G.E.; Hollema H.; Karrenbeld A.; Buys C.H.C.M.; van der Zee A.G.J.; Hofstra R.M.W.; Kleibeuker J.H.;
Am. J. Hum. Genet. 70:26-37(2002)
Cited for: VARIANTS CRC ILE-144; ARG-522; MET-725; CYS-850; ALA-878; ASP-1021; MET-1100; ILE-1219 AND ASP-1248;

MSH6 germline mutations are rare in colorectal cancer families.
Peterlongo P.; Nafa K.; Lerman G.S.; Glogowski E.; Shia J.; Ye T.Z.; Markowitz A.J.; Guillem J.G.; Kolachana P.; Boyd J.A.; Offit K.; Ellis N.A.;
Int. J. Cancer 107:571-579(2003)
Cited for: VARIANT CRC ALA-54; VARIANTS GLU-39; ALA-509; MET-854 AND ALA-878;

Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German hereditary nonpolyposis colorectal cancer consortium.
Plaschke J.; Engel C.; Krueger S.; Holinski-Feder E.; Pagenstecher C.; Mangold E.; Moeslein G.; Schulmann K.; Gebert J.; von Knebel Doeberitz M.; Rueschoff J.; Loeffler M.; Schackert H.K.;
J. Clin. Oncol. 22:4486-4494(2004)
Cited for: VARIANTS CRC ASN-99; ASP-619; VAL-787; ALA-878 AND CYS-1076;

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 THR-13; LEU-65; ILE-144; HIS-468; CYS-503; LEU-580; ALA-878; LEU-1232 AND GLY-1321;

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 VARIANT HNPCC5 VAL-20; CHARACTERIZATION OF VARIANTS CRC HIS-976 AND ASP-1021; CHARACTERIZATION OF VARIANTS SER-25; VAL-326; VAL-396; VAL-492; CYS-503; ARG-522; ASN-610; CYS-850; ALA-878; TYR-1026; SER-1087 AND MET-1225;

Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients.
Kantelinen J.; Kansikas M.; Candelin S.; Hampel H.; Smith B.; Holm L.; Kariola R.; Nystrom M.;
Hum. Mutat. 33:1294-1301(2012)
Cited for: CHARACTERIZATION OF VARIANTS PRO-435; PRO-585; THR-677; ALA-878; HIS-1095 AND GLN-1354;

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.