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UniProtKB/Swiss-Prot O96017: Variant p.Arg145Trp

Serine/threonine-protein kinase Chk2
Gene: CHEK2
Variant information

Variant position:  145
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
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 Arginine (R) to Tryptophan (W) at position 145 (R145W, p.Arg145Trp).
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 large size and basic (R) to large size and aromatic (W)
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

Involvement in disease:  Li-Fraumeni syndrome 2 (LFS2) [MIM:609265]: A highly penetrant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed (PubMed:8118819 and PubMed:8718514) and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers. {ECO:0000269|PubMed:11719428}. 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 colon cancer and LFS2; does not cause protein abrogation in familial colorectal cancer; loss of the ability to interact with and phosphorylate CDC25A and to promote CDC25A degradation in response to ionizing radiation.
Any additional useful information about the variant.

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

Sequence information

Variant position:  145
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  543
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.




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 1 – 543 Serine/threonine-protein kinase Chk2
Domain 113 – 175 FHA
Alternative sequence 1 – 221 Missing. In isoform 13.
Alternative sequence 75 – 392 Missing. In isoform 11.
Alternative sequence 107 – 487 Missing. In isoform 3.
Alternative sequence 107 – 197 Missing. In isoform 4.
Alternative sequence 131 – 147 KRTDKYRTYSKKHFRIF -> EFRSYSFYLP. In isoform 10.
Beta strand 144 – 150

Literature citations

The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis.
Falck J.; Mailand N.; Syljuaasen R.G.; Bartek J.; Lukas J.;
Nature 410:842-847(2001)

Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.
Bell D.W.; Varley J.M.; Szydlo T.E.; Kang D.H.; Wahrer D.C.R.; Shannon K.E.; Lubratovich M.; Versalis S.J.; Isselbacher K.J.; Fraumeni J.F. Jr.; Birch J.M.; Li F.P.; Garber J.E.; Haber D.A.;
Science 286:2528-2531(1999)

Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome.
Lee S.B.; Kim S.H.; Bell D.W.; Wahrer D.C.R.; Schiripo T.A.; Jorczak M.M.; Sgroi D.C.; Garber J.E.; Li F.P.; Nichols K.E.; Varley J.M.; Godwin A.K.; Shannon K.M.; Harlow E.; Haber D.A.;
Cancer Res. 61:8062-8067(2001)
Cited for: VARIANT LFS2 TRP-145;

Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility.
Schutte M.; Seal S.; Barfoot R.; Meijers-Heijboer H.; Wasielewski M.; Evans D.G.; Eccles D.; Meijers C.; Lohman F.; Klijn J.; van den Ouweland A.; Brady A.; Cole T.; Collins A.; Cox H.; Donaldson A.; Eeles R.; Evans G.; Gregory H.; Gray J.; Houlston R.; Lalloo F.; Lucassen A.; Mackay J.; Mitchell G.; Morrison P.; Murday V.; Narod S.; Patterson J.; Peretz T.; Phelan C.M.; Rogers M.; Schofield A.; Tonin P.; Weber B.; Weber W.; Futreal P.A.; Nathanson K.L.; Weber B.L.; Easton D.F.; Stratton M.R.; Rahman N.;
Am. J. Hum. Genet. 72:1023-1028(2003)
Cited for: VARIANTS GLY-117; TRP-145 AND THR-157;

Frequency of CHEK2 mutations in a population based, case-control study of breast cancer in young women.
Friedrichsen D.M.; Malone K.E.; Doody D.R.; Daling J.R.; Ostrander E.A.;
Breast Cancer Res. 6:R629-R635(2004)
Cited for: VARIANTS TRP-145 AND THR-157;

Homozygosity for a CHEK2*1100delC mutation identified in familial colorectal cancer does not lead to a severe clinical phenotype.
van Puijenbroek M.; van Asperen C.J.; van Mil A.; Devilee P.; van Wezel T.; Morreau H.;
J. Pathol. 206:198-204(2005)
Cited for: VARIANTS GLY-117; GLN-137; TRP-145; THR-157 AND HIS-180;

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.