BRAF G469A - GET-Evidence

Curation:
Currentness:

BRAF G469A

(BRAF Gly469Ala)


Short summary

BRAF (B-Raf proto-oncogene serine/threonine-protein kinase) G469A is a missense mutation within exon 11 of the BRAF gene. It is due to a mutation at nucleotide 1406 (GGA—>GCA) that lead to a an amino acid change from glycine to alanine ( G469A). BRAF mutations are present in numerous cancers, in about 15% of all tumors and at least one type of mutation is seen in about 90% of all malignant melanoma tumors. G469 is part of the tip of a glycine-rich loop that coordinates the active siteon BRAF which is involved with holding the protein in a stable confromation . A G—>A at residue position 469 interrupts the stable interaction of the activation segment and the inhibited (steady) state of the kinase. Thus, the disruption leads to new interactions that fold the kinase into a constitutively active state and results in unregulated cell activitiy. In general, the P loop and the activation loop are common mutational sites; such driver (activating) mutations identified in cancers are of high clinical utility because they can be targeted with drugs.

Variant evidence
Computational 3

Log R.E-value = 1.21
GOSS score = 0
SIFT score = 0
SIFT median information content = 2.79

See unpublished research (below).

Functional 2

Somatic mutation. This BRAF mutation causes high-activity of kinase because it disrupts many mechanisms in the RAS/RAF/MEK/ERK activation pathway. Preclinical data demonstrate that both the V600E and G469A mutation are activators that are associated with increased BRAF kinase activity and downstream ERK1/2 phosphorylation, thus being involved in malignant cancers.This is a pathway commonly mediating cancer progression. Mutation is present in a glycine rich loop residue. Confers 230-fold activated in human cancers, hypersensitive to 17-allylamino-17-demethoxygeldanamycin, a derivative of the antibiotic geldanamycin that is being studied in the treatment of cancer ( this derivative acts as an inhibitor of the Hsp90 protein which is expressed in tumors)
(http://cancerres.aacrjournals.org/content/65/23/10686.full)

Case/Control -

In one study with 697 patients with lung adenocarcinoma, BRAF mutations were present in 18 patients (3%; 95% CI, 2% to 4%). The BRAF mutations identified were V600E (50%), G469A (39%), and D594G (11%). BRAF mutations occurred in 3% of patients with lung adenocarcinoma and occur more commonly in current and former smokers. The conclusion was that the incidence of BRAF mutations other than V600E ( thus mutations such as G469A) is significantly higher in lung cancer than in melanoma. There were no significant differences in stage, sex, age, or Karnofsky performance status between patients with BRAF mutations and those with either EGFR or KRASmutations(10.1200/JCO.2010.33.1280)

Familial -1

No familial information. Common environmental factors may contribute more to disease risk than familial factors.

 
Clinical importance
Severity 3

Out of 697 patients with lung adenocarcinoma, 18 had mutations in BRAf, 39% of which were G469A mutations; patients with the mutation received only a partial response to adjuvant treatment. The response of this mutation to Braf inhibitors targeted a the common Braf V600E mutation is currently unknown.

Treatability 1

BRAF G469a localizated to the mitochondria; has high kinase activation due to mutton in the P-loop. MEK and ERK inhibitors such as sorefenib therapy do not stop mitochondrial localization. Still not possible to bloch the large surface interactions.
Reference: Mitochondrial Localization and Regulation of BRAFV600E in Thyroid Cancer: A Clinically Used RAF Inhibitor Is Unable to Block the Mitochondrial Activities of BRAFV600

Penetrance 1

Perhaps low or no penetrance of most BRAF mutations, especially G469A. It is not seen in high percentages in most cancers. Braf V600E, on the other hand, is highly penetrant mutation that is seen in more than half of all cancers, and in 90% of malignant melanomas. However, out of the 18 patients in one study that had mutations in Braf, 30% of them were G469 positive, leading to a conclusion that it is penetrant to a certain degree.

 

Impact

Low clinical importance, Uncertain pathogenic

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

BRAF mutations in general occur in about 3% of patients with lung adenocarcinoma and are more common in smokers. the v600E mutation is significant higher in melanoma patients, but mutations other than V600E are more common in lung cancers.
As stated above, out of 697 patients with lung adenocarcinoma, 18 had mutations in BRAf, 39% of which were G469A mutations; patients with the mutation received only a partial response to adjuvant treatment. The response of this mutation to Braf inhibitors targeted a the common Braf V600E mutation is currently unknown. However, the non-V600E mutations, however, could be targets for other Braf and ERK inhibitors. Cell lines with non-V600E mutations, such H1755 lung cancer cells with the G469A mutations, are resistant to the growth-suppressive effects of PLX4032 ( Vemurafenib). In fact, Braf mutations commonly render tumor resistance to many of the anti-cancer therapies.
B-Raf mutation G469A contributes to the progression of periampullary and ampullary adenomas and carcinomas. These cancers account for 5 % of all Gastrointestinal tumors. The KRAS and the G469A BRAF mutation occur simultaneously in one periampullary adenoma of duodenal origin (DOI 10.1007/s11605-009-0917-4)
It has been speculated that the presence of the CXCR2G354W allele might allow lung adenocarcinoma NCI-H1395 cells to bypass BRAF G469A-induced OIS (oncogene-induced senescence)
From a Braf mutation analysis test: Results showed that this specific mutation is also implicated in non-Hodgkin lymphoma, colorectal cancer, malignant melanoma ( small percentage), thyroid carcinoma, acute lymphoblastoid leukemia, non-small cell lung carcinoma, and adenocarcinoma of lung as previously mentioned. Mutations in BRAF codons 464-469 occur at a general frequency of10% across all these cancers (OMIM BRAF Mutation Analysis – Tumor Code 9000). Cardio-facio-cutaneous (CFC) syndrome has been implicated with eight BRAF mutations, one of which is G469A.

CanPredict: http://strubiol.icr.ac.uk/extra/mokca/aggregate.php?aggregate_id=110 for Computational
http://www.sciencedirect.com/science/article/pii/S0092867404002156
doi: 10.1200/JCO.2010.31.8923

Allele frequency

  • None available.

Publications
 

Lee MH, Lee SE, Kim DW, Ryu MJ, Kim SJ, Kim SJ, Kim YK, Park JH, Kweon GR, Kim JM, Lee JU, De Falco V, Jo YS, Shong M. Mitochondrial localization and regulation of BRAFV600E in thyroid cancer: a clinically used RAF inhibitor is unable to block the mitochondrial activities of BRAFV600E. J Clin Endocrinol Metab. 2011 Jan;96(1):E19-30. Epub 2010 Oct 6. PubMed PMID: 20926530.

 

Genomes
 

Other external references
 

    PolyPhen-2
  • Score: 0.902 (probably damaging)
    Web search results (97 hits -- see all)
  • MoKCa
    ... genes :: Mutations of BRAF :: G469A. BRAF G469A. Mutation type. Missense ... for this mutation is not correct, as G469A is known to be highly activating (LHP ...
    strubiol.icr.ac.uk/extra/mokca/aggregate.php?...
  • AutoGenomics INFINITI BRAF
    The INFINITI® BRAF Assay is designed to identify BRAF genetic mutations. ... Codon 569: G469A, G469E. Codon 597: L597R, L597V. Codon 601: K601E. 25-50ng DNA/reaction ...
    www.autogenomics.com/1/cancer_BRAF.php
  • Cancer Genome Project Data
    Mutations of the BRAF gene in human cancer. Davies H, Bignell GR, Cox ... p.G469A. NCI-H157. KRAS. p.G12R. NCI-H1666. BRAF. p.G466V. NCI-H1755. BRAF. p.G469A. NCI-H1792. KRAS ...
    sanger.ac.uk/perl/genetics/CGP/cgp_viewer?...&pmid=12068308
  • CRAF inhibition induces apoptosis in melanoma cells with non ...
    logical targeting of BRAF/MAPK signaling in melano- ma is now being ... Exon 11, G469A BRAF mutation. The next most. significant group of patients harbored ...
    www.wistar.org/Herlyn/Pub PDFs/2008/Smalley2008-3.pdf
  • Ampullary Cancer - Studies in the area of adenocarcinoma ...
    NewsRx provides Ampullary Cancer news and medical articles. ... missense mutations of BRAF (6%), one within exon 11 (G469A), and one V600E hot spot mutation in exon 15 of BRAF. ...
    www.newsrx.com/library/topics/Ampullary-Cancer/260672.html
  • Genetic Predictors of MEK Dependence in Non-Small Cell Lung ...
    Although BRAF is the kinase most frequently mutated in human tumors, the ... G469A BRAF mutation, suggesting that additional genetic heterogeneity within the ...
    cancerres.aacrjournals.org/cgi/content/full/68/22/9375
  • share.gene.com
    ... BRAF E586K BRAF F468C BRAF F583F BRAF F595L BRAF F595S BRAF G464E BRAF G464R BRAF G464V BRAF G466A BRAF G466E BRAF G466R BRAF G466V BRAF G469A ...
    share.gene.com/mutation_classification/cancer.variants.txt
  • Development and Applications of a BRAF Oligonucleotide ...
    Development and Applications of a BRAF Oligonucleotide Microarray ... SNU-18 thyroid cell line harboring the G469A mutation was obtained from the Korean Cell ...
    jmd.amjpathol.org/cgi/content/full/9/1/55
  • Catalogue of Somatic Mutations in Cancer
    haematopoietic and lymphoid tissue; NS; NS; NS. Primary Histology; ... BRAF. p.G469A. c.1406G>C. Confirmed somatic variant. Unknown. References. BRAF mutations in ...
    sanger.ac.uk/perl/genetics/CGP/cosmic?...
  • Development and Applications of a BRAF Oligonucleotide Microarray
    Development and Applications of a BRAF Oligonucleotide Microarray ... 18 thyroid cell line harboring the G469A mutation was obtained from the Korean ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC1867429

Other in silico analyses
 

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 6

Edit history
 

Gene search

"GENE" or "GENE A123C":

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