Variant information:

(Click the titles to show more information.)

Variant position: 858

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 Leucine (L) to Arginine (R) at position 858 (L858R, p.Leu858Arg).

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 (L) to large size and basic (R)

The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score: -2

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: Defects in EGFR are associated with lung cancer (LNCR) [MIM:211980]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.

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: Found in a lung cancer sample; somatic mutation; constitutively activated enzyme with strongly increased kinase activity.

Any additional useful information about the variant.

Other resources: 

Links to websites of interest for the variant.

• GeneReviews
• NIEHS-SNPs
• Wikipedia; EGFR entry

Sequence information:

(Click the titles to show more information.)

Variant position: 858

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

Protein sequence length: 1210

The length of the canonical sequence.

Location on the sequence:  LAARNVLVKTPQHVKITDFG  L AKLLGAEEKEYHAEGGKVPI

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                         LAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPI

Mouse                         LAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPI

Drosophila                    LAARNVLVQTPSLVKITDFGLAKLLSSDSNEYKAAGGKMPI

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	25 – 1210	Epidermal growth factor receptor
Topological domain	669 – 1210	Cytoplasmic
Domain	712 – 979	Protein kinase
Binding site	855 – 855	ATP
Cross	867 – 867	Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Alternative sequence	406 – 1210	Missing. In isoform 2.
Alternative sequence	629 – 1210	Missing. In isoform 4.
Alternative sequence	706 – 1210	Missing. In isoform 3.
Helix	858 – 862

Literature citations

Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity.
Yun C.H.; Boggon T.J.; Li Y.; Woo M.S.; Greulich H.; Meyerson M.; Eck M.J.;
Cancer Cell 11:217-227(2007)
Cited for: X-RAY CRYSTALLOGRAPHY (2.47 ANGSTROMS) OF 696-1022 OF WILD-TYPE AND VARIANTS SER-719 AND ARG-858 IN COMPLEXES WITH ATP ANALOGS AND SYNTHETIC INHIBITORS; CATALYTIC ACTIVITY; AUTOPHOSPHORYLATION; CHARACTERIZATION OF VARIANTS SER-719 AND ARG-858;

Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity.
Yun C.H.; Boggon T.J.; Li Y.; Woo M.S.; Greulich H.; Meyerson M.; Eck M.J.;
Cancer Cell 11:217-227(2007)
Cited for: X-RAY CRYSTALLOGRAPHY (2.47 ANGSTROMS) OF 696-1022 OF WILD-TYPE AND VARIANTS SER-719 AND ARG-858 IN COMPLEXES WITH ATP ANALOGS AND SYNTHETIC INHIBITORS; CATALYTIC ACTIVITY; AUTOPHOSPHORYLATION; CHARACTERIZATION OF VARIANTS SER-719 AND ARG-858;

EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.
Paez J.G.; Janne P.A.; Lee J.C.; Tracy S.; Greulich H.; Gabriel S.; Herman P.; Kaye F.J.; Lindeman N.; Boggon T.J.; Naoki K.; Sasaki H.; Fujii Y.; Eck M.J.; Sellers W.R.; Johnson B.E.; Meyerson M.;
Science 304:1497-1500(2004)
Cited for: VARIANTS SER-719 AND ARG-858; POSSIBLE INVOLVEMENT IN LUNG CANCER;

Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features.
Tam I.Y.S.; Chung L.P.; Suen W.S.; Wang E.; Wong M.C.M.; Ho K.K.; Lam W.K.; Chiu S.W.; Girard L.; Minna J.D.; Gazdar A.F.; Wong M.P.;
Clin. Cancer Res. 12:1647-1653(2006)
Cited for: VARIANTS ALA-709; LYS-709; ALA-719; ASP-719; CYS-719; SER-719; SER-724; LYS-734; GLU-746 DEL; PHE-747; 747-LEU--GLU-749 DEL; PRO-748; 752-SER--ILE-759 DEL; ARG-787; MET-790; VAL-833; LEU-834; MET-858; ARG-858; GLN-861 AND GLU-873; POSSIBLE INVOLVEMENT IN LUNG CANCER;