BRAF
|
class 1
|
unknown |
gain of function |
BRAF Class 1 variants are BRAF variants that activate BRAF and downstream signaling in a dimer-independent, RAS-independent manner (PMID: 28783719, PMID: 26343582). |
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BRAF
|
class 2
|
unknown |
gain of function |
BRAF Class 2 variants are BRAF variants that activate BRAF and downstream signaling in a dimer-dependent, RAS-independent manner (PMID: 28783719, PMID: 26343582). |
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BRAF
|
class 3
|
unknown |
loss of function |
BRAF Class 3 variants are BRAF variants that demonstrate low or no BRAF kinase activity, but activate downstream signaling through CRAF activation, in a dimer-dependent, RAS-dependent manner (PMID: 28783719). |
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BRAF
|
D287H
|
missense |
loss of function |
BRAF D287H does not lie within any known functional domains of the Braf protein (UniProt.org). D287H results in impaired Braf kinase activity, but leads to Ras-dependent activation of Erk in cell culture (PMID: 26343582, PMID: 28783719). |
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BRAF
|
D594A
|
missense |
loss of function |
BRAF D594A lies within the protein kinase domain of the Braf protein (UniProt.org). D594A results in a lack of Braf kinase activity (PMID: 20141835, PMID: 20978199, PMID: 28783719), promotes aneupolidy (PMID: 20978199), and in one of two cell lines demonstrated decreased transformation ability compared to wild-type Braf in culture (PMID: 29533785), but leads to activation of Mek and Erk through cooperation with activated RAS and transactivation of CRAF in cell culture and mouse models (PMID: 20141835, PMID: 20978199, PMID: 28783719). |
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BRAF
|
D594E
|
missense |
loss of function |
BRAF D594E lies within the protein kinase domain of the Braf protein (UniProt.org). D594E results in impaired Braf kinase activity, however, results in increased Mek and Erk phosphorylation in the presence of CRAF in cell culture (PMID: 28783719). |
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BRAF
|
D594G
|
missense |
unknown |
BRAF D594G lies within the protein kinase domain of the Braf protein (UniProt.org). D594G has been demonstrated to result in impaired Braf kinase activity, but leads to increased activation of Erk signaling through CRAF in cell culture (PMID: 18794803, PMID: 28783719), has also been shown to result in CRAF activation similar to wild-type Braf but with enhanced dimerization and the ability to bypass autoinhibitory autophosphorylation in in vitro assays (PMID: 31929109), however, has increased transforming ability in one of two cell lines in culture (PMID: 29533785), and confers Mek inhibitor resistance in culture (PMID: 18794803), and therefore, its effect on Braf protein function is unknown. |
Y |
BRAF
|
D594H
|
missense |
loss of function - predicted |
BRAF D594H lies within the protein kinase domain of the Braf protein (UniProt.org). D594H results in a loss of Braf kinase activity, but leads to Ras-dependent activation of Erk signaling through CRAF (PMID: 28783719), and demonstrates decreased transforming activity compared to wild-type Braf in one of two cell lines in culture (PMID: 29533785), and therefore is predicted to confer a loss of function to the Braf protein. |
|
BRAF
|
D594N
|
missense |
loss of function - predicted |
BRAF D594N lies within the protein kinase domain of the Braf protein (UniProt.org). D594N results in impaired Braf kinase activity, but leads to activation of Erk signaling through CRAF in cell culture (PMID: 28783719), and demonstrates decreased transforming ability compared to wild-type Braf in one of two cell lines in culture (PMID: 29533785), and therefore is predicted to confer a loss of function to the Braf protein. |
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BRAF
|
F595L
|
missense |
loss of function |
BRAF F595L lies within the protein kinase domain of the Braf protein (UniProt.org). F595L results in reduced Braf kinase activity (PMID: 28783719, PMID: 15035987), but works cooperatively with oncogenic Ras to activate MEK/ERK signaling, and is transforming in cell culture (PMID: 15035987, PMID: 26582644, PMID: 29533785). |
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BRAF
|
G466A
|
missense |
unknown |
BRAF G466A (also reported as G465A) lies within the protein kinase domain of the Braf protein (UniProt.org). The functional effect of G466A (also reported as G465A) is conflicting as it has been characterized both as having intermediate Braf kinase activity (PMID: 15035987) and low Braf kinase activity (PMID: 28783719), leads to Ras-dependent activation of downstream Erk in cell culture (PMID: 28783719), and in one of two cell lines increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785). |
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BRAF
|
G466V
|
missense |
loss of function |
BRAF G466V lies within the protein kinase domain of the Braf protein (UniProt.org). G466V results in impaired Braf kinase activity, but paradoxically activates MEK and ERK through transactivation of CRAF in cell culture (PMID: 22649091, PMID: 28783719), and in one of two cell lines, G466V decreased cell proliferation and cell viability as compared to wild-type Braf (PMID: 29533785). |
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BRAF
|
G469E
|
missense |
unknown |
BRAF G469E is a hotspot mutation that lies within the protein kinase domain of the Braf protein (UniProt.org). G469E results in decreased Braf kinase activity (PMID: 28783719, PMID: 15035987), but leads to Ras-dependent activation of Erk signaling in cell culture (PMID: 28783719, PMID: 33795686), and results in increased cell proliferation and cell viability as compared to wild-type Braf in one of two cell lines (PMID: 29533785), and confers Mek inhibitor resistance in culture (PMID: 18794803), and therefore, its effect on Braf protein function is unknown. |
Y |
BRAF
|
G469R
|
missense |
gain of function - predicted |
BRAF G469R is a hotspot mutation within the protein kinase domain of the Braf protein (UniProt.org). G469R demonstrates intermediate BRAF kinase activity (PMID: 28783719) and results in constitutive ERK activation in cell culture (PMID: 24920063), and in one of two cell lines leads to increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785), and is therefore predicted to confer a gain of function to the Braf protein. |
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BRAF
|
G469V
|
missense |
gain of function |
BRAF G469V is a hotspot mutation within the protein kinase domain of the Braf protein (UniProt.org). G469V results in increased Braf kinase activity and activation of downstream MEK and ERK in cell culture (PMID: 28947956, PMID: 26343582, PMID: 28783719), and in one of two cell lines, increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785). |
|
BRAF
|
G596D
|
missense |
unknown |
BRAF G596D lies within the protein kinase domain of the Braf protein (UniProt.org). G596D demonstrates decreased Braf kinase activity in one study (PMID: 28783719), but results in increased Erk phosphorylation in another study, and is associated with resistance to Raf inhibitors (PMID: 31158244), and therefore, its effect on Braf protein function is unknown. |
Y |
BRAF
|
G596R
|
missense |
loss of function - predicted |
BRAF G596R lies within the protein kinase domain of the Braf protein, within the DFG motif (PMID: 19735675). G596R results in impaired Braf kinase activity and decreased Mek and Erk phosphorylation, including in the presence of BRAF V600E, is not transforming in culture and does not promote tumor formation in mouse models, but results in activation of Erk in the presence of CRAF (PMID: 19735675, PMID: 28783719), however, in another study demonstrates similar cell proliferation and viability levels to wild-type Braf (PMID: 29533785), and is predicted to confer a loss of function to the Braf protein. |
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BRAF
|
K601E
|
missense |
gain of function |
BRAF K601E lies within the activation segment in the kinase domain of the Braf protein (PMID: 15343278). K601E results in increased Braf kinase activity and downstream activation of MEK and ERK in cell culture (PMID: 22798288, PMID: 28783719, PMID: 32059434), and induces cell proliferation and cell viability in culture (PMID: 29533785). |
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BRAF
|
K601T
|
missense |
gain of function - predicted |
BRAF K601T lies within the activation segment in the kinase domain of the Braf protein (PMID: 15343278). K601T results in increased Braf kinase activity in cell culture (PMID: 28783719), and in one of two cell lines increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785), and is therefore predicted to confer a gain of function to the Braf protein. |
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BRAF
|
N581I
|
missense |
unknown |
BRAF N581I lies within the protein kinase domain of the Braf protein (UniProt.org). N581I results in low Braf kinase activity and Ras-dependent activation of Erk signaling in cell culture (PMID: 28783719), however, also results in increased transformation ability compared to wild-type Braf in culture (PMID: 29533785), and therefore, its effect on Braf protein function is unknown. |
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BRAF
|
N581S
|
missense |
unknown |
BRAF N581S lies within the protein kinase domain of the Braf protein (UniProt.org). The functional effect of N581S is unknown as it has been demonstrated to result in intermediate Braf kinase activity (PMID: 15035987), as well as low Braf kinase activity (PMID: 28783719), and results in Ras-dependent activation of Erk signaling in cell culture (PMID: 28783719), however in another study, demonstrated increased transformation ability in one of two different cell lines compared to wild-type Braf (PMID: 29533785), and has been identified as a secondary resistance mutation (PMID: 32553555). |
Y |
BRAF
|
S467L
|
missense |
unknown |
BRAF S467L lies within the protein kinase domain of the Braf protein (UniProt.org). S467L results in impaired Braf kinase activity, but leads to Ras-dependent activation of Erk in cell culture (PMID: 28783719), and increased cell proliferation and cell viability as compared to wild-type Braf in two different cell lines (PMID: 29533785), and therefore, its effect on Braf protein function is unknown. |
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BRAF
|
T529M
|
missense |
unknown |
BRAF T529M lies within the protein kinase domain of the Braf protein (UniProt.org). T529M has been demonstrated to confer resistance to Raf inhibitors (PMID: 20538618, PMID: 28783719, PMID: 31453322), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Nov 2022). |
Y |
BRAF
|
V459L
|
missense |
unknown |
BRAF V459L lies within the protein kinase domain of the Braf protein (UniProt.org). V459L results in impaired Braf kinase activity and leads to Ras-dependent activation of Erk in culture (PMID: 28783719), however, in two different cell lines, induces similar cell proliferation and cell viability as compared to wild-type Braf (PMID: 29533785), and therefore, its effect on Braf protein function is unknown. |
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BRAF
|
V600M
|
missense |
gain of function - predicted |
BRAF V600M (previously reported as V599) lies within the activation segment of the kinase domain of the Braf protein (PMID: 15035987). V600M results in intermediate Braf kinase activity in cell culture (PMID: 28783719), and in one of two cell lines increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785), and is therefore predicted to confer a gain of function to the Braf protein. |
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