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UniProtKB/Swiss-Prot P42336: Variant p.Glu545Lys

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Gene: PIK3CA
Variant information

Variant position:  545
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 Glutamate (E) to Lysine (K) at position 545 (E545K, p.Glu545Lys).
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 acidic (E) to large size and basic (K)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  1
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:  Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) [MIM:602501]: A syndrome characterized by a spectrum of anomalies including primary megalencephaly, prenatal overgrowth, brain and body asymmetry, cutaneous vascular malformations, digital anomalies consisting of syndactyly with or without postaxial polydactyly, connective tissue dysplasia involving the skin, subcutaneous tissue, and joints, and cortical brain malformations, most distinctively polymicrogyria. {ECO:0000269|PubMed:22729224, ECO:0000269|PubMed:26593112}. 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:  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:15930273, ECO:0000269|PubMed:15994075}. Note=The gene represented in this entry may be involved in disease pathogenesis.
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:  Keratosis, seborrheic (KERSEB) [MIM:182000]: A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance. {ECO:0000269|PubMed:17673550}. 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:  Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:16353168}. 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 MCAP, KERSEB, CRC and BC; shows an increase in lipid kinase activity; oncogenic in vivo; occurs in the interface between the PI3K helical domain and the nSH2 (N-terminal SH2) region of the p85 regulatory subunit and may reduce the inhibitory effect of p85; requires interaction with RAS to induce cellular transformation; enhances invadopodia-mediated extracellular matrix degradation and invasion in breast cancer cells.
Any additional useful information about the variant.

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



Sequence information

Variant position:  545
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  1068
The length of the canonical sequence.

Location on the sequence:   ENDKEQLKAISTRDPLSEIT  E QEKDFLWSHRHYCVTIPEIL
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                         ENDKEQLKAISTRDPLSEITEQEKDFLWSHRHYCVTIPEIL

Mouse                         ENDKEQLRALCTRDPLSEITEQEKDFLWSHRHYCVTIPEIL

Rat                           ENDKEQLRALCTRDPLSEITEQEKDFLWSHRHYCVTIPEIL

Bovine                        ENDKEQLRAICTRDPLSEITEQEKDFLWSHRHYCVTIPEIL

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 – 1068 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Domain 517 – 694 PIK helical
Helix 545 – 553


Literature citations

Phosphoinositide 3-kinase signaling pathway mediated by p110{alpha} regulates invadopodia formation.
Yamaguchi H.; Yoshida S.; Muroi E.; Yoshida N.; Kawamura M.; Kouchi Z.; Nakamura Y.; Sakai R.; Fukami K.;
J. Cell Biol. 193:1275-1288(2011)
Cited for: FUNCTION IN INVADOPODIA FORMATION; CHARACTERIZATION OF VARIANTS LYS-545 AND ARG-1047;

Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas.
Broderick D.K.; Di C.; Parrett T.J.; Samuels Y.R.; Cummins J.M.; McLendon R.E.; Fults D.W.; Velculescu V.E.; Bigner D.D.; Yan H.;
Cancer Res. 64:5048-5050(2004)
Cited for: VARIANTS CANCER LYS-542; LYS-545; PRO-546; ASN-1021; ARG-1047; LEU-1047 AND TYR-1065;

Mutation of the PIK3CA gene in ovarian and breast cancer.
Campbell I.G.; Russell S.E.; Choong D.Y.H.; Montgomery K.G.; Ciavarella M.L.; Hooi C.S.F.; Cristiano B.E.; Pearson R.B.; Phillips W.A.;
Cancer Res. 64:7678-7681(2004)
Cited for: INVOLVEMENT IN OC; VARIANTS CANCER GLY-545; LYS-545; LYS-546; GLU-546; ARG-1047 AND LEU-1047;

Mutations of PIK3CA in gastric adenocarcinoma.
Li V.S.W.; Wong C.W.; Chan T.L.; Chan A.S.W.; Zhao W.; Chu K.-M.; So S.; Chen X.; Yuen S.T.; Leung S.Y.;
BMC Cancer 5:29-29(2005)
Cited for: VARIANTS CANCER LYS-542; LYS-545 AND ARG-1047;

Functional analysis of PIK3CA gene mutations in human colorectal cancer.
Ikenoue T.; Kanai F.; Hikiba Y.; Obata T.; Tanaka Y.; Imamura J.; Ohta M.; Jazag A.; Guleng B.; Tateishi K.; Asaoka Y.; Matsumura M.; Kawabe T.; Omata M.;
Cancer Res. 65:4562-4567(2005)
Cited for: INVOLVEMENT IN CRC; CHARACTERIZATION OF VARIANTS CRC HIS-38; VAL-106; ARG-420; GLN-453; LYS-542; LYS-545; ILE-1043 AND ARG-1047;

High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma.
Oda K.; Stokoe D.; Taketani Y.; McCormick F.;
Cancer Res. 65:10669-10673(2005)
Cited for: VARIANTS CANCER GLN-542; LYS-542; GLY-545; LYS-545; ARG-1007; HIS-1021; CYS-1021; VAL-1035; ILE-1043; TYR-1047; ARG-1047; ASP-1050; LYS-1052 AND LEU-1065;

The prevalence of PIK3CA mutations in gastric and colon cancer.
Velho S.; Oliveira C.; Ferreira A.; Ferreira A.C.; Suriano G.; Schwartz S. Jr.; Duval A.; Carneiro F.; Machado J.C.; Hamelin R.; Seruca R.;
Eur. J. Cancer 41:1649-1654(2005)
Cited for: INVOLVEMENT IN CRC; VARIANTS CANCER LYS-542; GLY-545; LYS-545; GLN-1023; ARG-1047 AND LEU-1047;

PIK3CA mutations in advanced ovarian carcinomas.
Wang Y.; Helland A.; Holm R.; Kristensen G.B.; Boerresen-Dale A.-L.;
Hum. Mutat. 25:322-322(2005)
Cited for: VARIANTS CANCER LYS-545 AND ARG-1047;

PIK3CA mutations in head and neck squamous cell carcinoma.
Qiu W.; Schoenleben F.; Li X.; Ho D.J.; Close L.G.; Manolidis S.; Bennett B.P.; Su G.H.;
Clin. Cancer Res. 12:1441-1446(2006)
Cited for: VARIANTS CANCER CYS-343; LYS-542; LYS-545 AND ARG-1047; VARIANT MET-391;

PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma.
Buttitta F.; Felicioni L.; Barassi F.; Martella C.; Paolizzi D.; Fresu G.; Salvatore S.; Cuccurullo F.; Mezzetti A.; Campani D.; Marchetti A.;
J. Pathol. 208:350-355(2006)
Cited for: VARIANTS BC LYS-542; VAL-542; LYS-545; ARG-546; ARG-1047 AND LEU-1047;

Cancer-specific mutations in PIK3CA are oncogenic in vivo.
Bader A.G.; Kang S.; Vogt P.K.;
Proc. Natl. Acad. Sci. U.S.A. 103:1475-1479(2006)
Cited for: CHARACTERIZATION OF VARIANTS CANCER LYS-542; LYS-545 AND ARG-1047;

Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern.
Hafner C.; Lopez-Knowles E.; Luis N.M.; Toll A.; Baselga E.; Fernandez-Casado A.; Hernandez S.; Ribe A.; Mentzel T.; Stoehr R.; Hofstaedter F.; Landthaler M.; Vogt T.; Pujol R.M.; Hartmann A.; Real F.X.;
Proc. Natl. Acad. Sci. U.S.A. 104:13450-13454(2007)
Cited for: VARIANTS KERSEB LYS-542; LYS-545; GLY-545 AND ARG-1047;

De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.
Riviere J.B.; Mirzaa G.M.; O'Roak B.J.; Beddaoui M.; Alcantara D.; Conway R.L.; St-Onge J.; Schwartzentruber J.A.; Gripp K.W.; Nikkel S.M.; Worthylake T.; Sullivan C.T.; Ward T.R.; Butler H.E.; Kramer N.A.; Albrecht B.; Armour C.M.; Armstrong L.; Caluseriu O.; Cytrynbaum C.; Drolet B.A.; Innes A.M.; Lauzon J.L.; Lin A.E.; Mancini G.M.; Meschino W.S.; Reggin J.D.; Saggar A.K.; Lerman-Sagie T.; Uyanik G.; Weksberg R.; Zirn B.; Beaulieu C.L.; Majewski J.; Bulman D.E.; O'Driscoll M.; Shendure J.; Graham J.M. Jr.; Boycott K.M.; Dobyns W.B.;
Nat. Genet. 44:934-940(2012)
Cited for: VARIANTS MCAP LYS-81; GLN-88; ARG-364; LYS-365; TYR-378; GLU-453 DEL; LYS-545; LYS-726; ARG-914; CYS-1021; ALA-1025; VAL-1035; ILE-1043; TYR-1047 AND SER-1049;

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.