Gene Detail

Gene Symbol RET
Synonyms CDHF12 | CDHR16 | HSCR1 | MEN2A | MEN2B | MTC1 | PTC | RET-ELE1
Gene Description RET, ret proto-oncogene, is a receptor tyrosine kinase that activates MAPK and PI3K/AKT pathways and regulates cell growth and differentiation (PMID: 24561444, PMID: 29134959). RET germline mutations result in MEN2 syndromes and familial medullary thyroid carcinoma (PMID: 20930041, PMID: 24561444) and somatic RET activating mutations, fusions, and Ret overexpression has been associated with a variety of cancers including lung (PMID: 30257958) and colorectal (PMID: 30210625, PMID: 30038711).
ACMG Incidental List v2.0:
Yes, Multiple endocrine neoplasia, type 2a (PMID: 27854360)
Yes, Familial medullary thyroid carcinoma (PMID: 27854360)
Yes, Multiple endocrine neoplasia, type 2b (PMID: 27854360)
Entrez Id 5979
Chromosome 10
Map Location 10q11.21
Canonical Transcript NM_020975

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Variant Impact Protein Effect Variant Description Associated with drug Resistance
C620F missense unknown RET C620F lies within the extracellular domain of the Ret protein (UniProt.org). C620F has been identified in the scientific literature (PMID: 21765987, PMID: 25694125, PMID: 16705552), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
R813Q missense loss of function RET R813Q lies within the protein kinase domain of the Ret protein (UniProt.org). R813Q results in decreased Ret, Erk, and Mapk phosphorylation, reduced cell migration and colony formation compared to wild-type Ret protein in culture (PMID: 22729463, PMID: 22837065).
C611W missense gain of function - predicted RET C611W lies within the extracellular domain of the Ret protein (UniProt.org). C611W has not been fully biochemically characterized, but is transforming in cell culture (PMID: 9230192), thus is predicted to confer a gain of function on the Ret protein.
T1038A missense unknown RET T1038A does not lie within any known functional domains of the Ret protein (UniProt.org). T1038Ahas been identified in the scientific literature (PMID: 29263839, PMID: 29642553), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Sep 2018).
L790F missense unknown RET L790F lies within the protein kinase domain of the Ret protein (UniProt.org). The functional effect of L790F is conflicting, as L790F has been reported to result in ligand-independent activation of Ret (PMID: 15184865), but also to display growth promotion and transforming activity similar to wild-type Ret protein (PMID: 21810974).
L923H missense unknown RET L923H lies within the protein kinase domain of the Ret protein (UniProt.org). L923H has been identified in sequencing studies (PMID: 25148578), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
D631_L633delinsE indel unknown RET D631_L633delinsE results in a deletion of three amino acids in the extracellular domain of the Ret protein from amino acids 631 to 633, combined with the insertion of a glutamic acid (E) at the same site (UniProt.org). D631_L633delinsE has been identified in sequencing studies (PMID: 27082517), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
R77L missense unknown RET R77L lies within the extracellular domain of the Ret protein (UniProt.org). R77L has been identified in the scientific literature (PMID: 27372520), but has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
Y806E missense unknown RET Y806E lies within the protein kinase domain of the Ret protein (UniProt.org). Y806E has been demonstrated to occur as a secondary drug resistance mutation in the context of other RET activating mutations (PMID: 19029224), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2018). Y
Y806N missense unknown RET Y806N lies within the protein kinase domain of the Ret protein (UniProt.org). Y806N has been demonstrated to confer drug resistance in the context of KIF5B-RET in culture (PMID: 29908090), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2018). Y
A883X missense unknown RET A883X indicates any Ret missense mutation that results in replacement of the alanine (A) at amino acid 883 by a different amino acid.
F998V missense unknown RET F998V lies within the protein kinase domain of the Ret protein (UniProt.org). F998V has been demonstrated to confer drug resistance in the context of KIF5B-RET in culture (PMID: 29908090), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2018). Y
C609S missense gain of function - predicted RET C609S lies within the extracellular domain of the Ret protein (UniProt.org). C609S is predicted to confer a gain of function on the Ret protein, as demonstrated by ligand-independent Ret autophosphorylation in culture in one study (PMID: 16343103).
S891X missense unknown RET S891X indicates any Ret missense mutation that results in replacement of the serine (S) at amino acid 891 by a different amino acid.
S649L missense gain of function RET S649L lies within the transmembrane domain of the Ret protein (UniProt.org). S649L confers a gain of function to the Ret protein as demonstrated by constitutive kinase activity, increased cell proliferation compared to control, and transformation in culture (PMID: 18322301).
V871I missense unknown RET V871I lies within the protein kinase domain of the Ret protein (UniProt.org). V871I has been demonstrated to confer drug resistance in the context of KIF5B-RET in culture (PMID: 29908090), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018). Y
E632_T636delinsSS indel unknown RET E632_T636delinsSS results in the deletion of 5 amino acids in the Ret protein from amino acids 632 to 636, combined with the insertion of two serines (S) at the same site (UniProt.org). E632_T636delinsSS has been identified in the scientific literature (PMID: 9160884), but has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
R982C missense no effect - predicted RET R982C lies within the protein kinase domain of the Ret protein (UniProt.org). R982C demonstrates GDNF-dependent Mapk activation to similar level of wild-type Ret in culture (PMID: 22729463) and therefore, is predicted to have no effect on Ret protein function.
E921K missense loss of function RET E921K lies within the protein kinase domain of the Ret protein (UniProt.org). E921K results in a loss of ligand-dependent phosphorylation of Ret and downstream signaling molecules including Erk, Akt, and PLCgamma, is not transforming in culture (PMID: 11438491), and also abolishes the function of a concurring activating IDH1 mutation (C634R) in culture (PMID: 9502784, PMID: 17599050).
over exp none no effect RET over exp indicates an over expression of the Ret protein. However, the mechanism causing the over expression is unspecified.
R912Q missense loss of function RET R912Q lies within the protein kinase domain of the Ret protein (UniProt.org). R912Q results in decreased phosphorylation of Ret and Erk1/2, decreased migration and colony formation compared to wild-type Ret protein in culture (PMID: 22837065).
S936F missense unknown RET S936F lies within the protein kinase domain of the Ret protein (UniProt.org). S936F has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
L517V missense unknown RET L517V lies within the extracellular domain of the Ret protein (UniProt.org). L517V has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
T278S missense unknown RET T278S lies within the extracellular domain of the Ret protein (UniProt.org). T278S has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
T338I missense unknown RET T338I lies within the extracellular domain of the Ret protein (UniProt.org). T338I results in increased cell proliferation, but is not transforming in cell culture (PMID: 21810974).
C609F missense unknown RET C609F lies within the extracellular domain of the Ret protein (UniProt.org). C609F has been identified in the scientific literature (PMID: 9068588, PMID: 24699901), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
C618R missense gain of function RET C618R lies within the cysteine-rich region of the Ret protein (PMID: 9879991). C618R results in constitutive Ret phosphorylation and increased Ret kinase activity, but decreased Ret cell surface expression, and is transforming in cell culture (PMID: 9230192, PMID: 9879991).
C634R missense gain of function RET C634R lies within the extracellular domain of the Ret protein (UniProt.org). C634R results in autophosphorylation of Ret, and is transforming in cultured cells (PMID: 9242375, PMID: 10679286).
P273L missense unknown RET P273L lies within the extracellular domain of the Ret protein (UniProt.org). P273L has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
E623_L633del deletion unknown RET E623_L633del results in the deletion of eleven amino acids in the extracellular domain of the Ret protein from amino acids 623 to 633 (UniProt.org). E623_L633del has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
S765P missense loss of function RET S765P lies within the protein kinase domain of the Ret protein (UniProt.org). S765P results in a loss of ligand-dependent phosphorylation of Ret and downstream signaling molecules including Erk, Akt, and PLCgamma, is not transforming in culture, and abolishes the activity of a concurring activating IDH1 mutation (C634R) in culture (PMID: 11438491).
M1064T missense unknown RET M1064T lies within the cytoplasmic domain of the Ret protein (UniProt.org). M1064T does not affect the function of a concurring activating RET mutation (C634R) in culture (PMID: 9502784), but has not been characterized individually and therefore, its effect on Ret protein function is unknown (PubMed, Oct 2018).
L790X missense unknown RET L790X indicates any Ret missense mutation that results in replacement of the leucine (L) at amino acid 790 by a different amino acid.
A919V missense unknown RET A919V lies within the protein kinase domain of the Ret protein (UniProt.org). A919V has not been characterized, but is predicted to result in decreased Ret protein stability in computational models (PMID: 16928683, PMID: 19186126).
G533C missense gain of function RET G533C lies within the extracellular domain of the Ret protein (UniProt.org). G553C results in Ret autophosphorylation and increased Erk phosphorylation, enhanced cell proliferation, micronuclei formation, and colony formation, decreased apoptosis and expression of thyroid-specific genes in culture, and increased liver metastasis in mouse models (PMID: 21834681).
A1105V missense no effect - predicted RET A1105V lies within the cytoplasmic domain of the Ret protein (UniProt.org). A1105V demonstrates GDNF-dependent Mapk activation to similar level of wild-type Ret in culture (PMID: 22729463) and therefore, is predicted to have no effect on Ret protein function.
Y806C missense gain of function - predicted RET Y806C lies within the protein kinase domain of the Ret protein (UniProt.org). Y806C is predicted to lead to a gain of Ret protein function as indicated by transformation of cultured cells in one study (PMID: 10679286), and has also been demonstrated to occur as a secondary resistance mutation in conjunction with other RET mutations (PMID: 19029224). Y
E768D missense gain of function RET E768D lies within the protein kinase domain of the Ret protein (UniProt.org). E768D results in increased Ret autophosphorylation and is transforming in cell culture (PMID: 10445857).
E632K missense unknown RET E632K lies within the extracellular domain of the Ret protein (UniProt.org). E632K has been identified in sequencing studies (PMID: 22842228, PMID: 27756406), and lacks transforming activity as determined by in vitro and in silico tests (Tacito et al, Thyroid World Congress).
C611G missense unknown RET C611G lies within the extracellular domain of the Ret protein (UniProt.org). C611G has been identified in the scientific literature (PMID: 9677065), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
C630F missense gain of function RET C630F lies within the cysteine-rich region of the Ret protein (PMID: 9879991). C630F confers a gain of function on the Ret protein as indicated by Ret dimerization and transformation of cultured cells (PMID: 9230192).
C620W missense unknown RET C620W lies within the extracellular domain of the Ret protein (UniProt.org). C620W has been identified in the scientific literature (PMID: 9068588, PMID: 25163725), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
G810S missense unknown RET G810S lies within the protein kinase domain of the Ret protein (UniProt.org). G810S has been demonstrated to confer drug resistance in the context of KIF5B-RET in culture (PMID: 29908090), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2018). Y
S891L missense unknown RET S891L lies within the protein kinase domain of the Ret protein (UniProt.org). S891L has been identified in sequencing studies (PMID: 29615459, PMID: 26286987), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
V738A missense unknown RET V738A lies within the protein kinase domain of the Ret protein (UniProt.org). V738A has been demonstrated to confer drug resistance in the context of KIF5B-RET in culture (PMID: 29908090), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2018). Y
F612_C620del deletion unknown RET F612_C620del results in the deletion of nine amino acids in the extracellular domain of the Ret protein from amino acids 612 to 620 (UniProt.org). F612_C620del has been identified in sequencing studies (PMID: 25157968, PMID: 9587071), but has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
A756V missense unknown RET A756V lies within the protein kinase domain of the Ret protein (UniProt.org). A756V has been identified in sequencing studies (PMID: 27683183), but has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Oct 2018).
E623K missense unknown RET E623K lies within the extracellular domain of the Ret protein (UniProt.org). E623K has been identified in the scientific literature (PMID: 16849421, PMID: 15858153), but has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
R770Q missense unknown RET R770Q lies within the protein kinase domain of the Ret protein (UniProt.org). R770Q has been identified in the scientific literature (PMID: 20013610, PMID: 25425582), but has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
P973L missense loss of function - predicted RET P973L lies within the protein kinase domain of the Ret protein (UniProt.org). P973L results in decreased Ret mRNA and protein levels in culture in one study (PMID: 11438491) and therefore, is predicted to lead to a loss of Ret protein function.
V253E missense unknown RET V253E lies within the cadherin domain of the Ret protein (UniProt.org). V253E has been identified in sequencing studies (PMID: 28606923), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
L633_C634dup duplication gain of function RET L633_C634dup (also referred to as L633_C634insCRT) indicates the insertion of 3 duplicate amino acids, leucine (L)-633 through cystine(C)-634, in the extracellular domain of the Ret protein (UniProt.org). L633_C634dup results in ligand independent dimerization and constitutive activation of Ret in culture (PMID: 10918602).
C630G missense unknown RET C630G lies within the cysteine-rich region of the Ret protein (PMID: 9879991). C630G has been identified in sequencing studies (PMID: 19401695), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Oct 2018).
R77H missense unknown RET R77H lies within the extracellular domain of the Ret protein (UniProt.org). R77H has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
E734K missense loss of function RET E734K lies within the protein kinase domain of the Ret protein (UniProt.org). E734K results in a loss of phosphorylation of Ret and downsream signaling molecules including Erk1/2 and Stat3, decreased migration, colony formation, and response to GDNF-regulated apoptosis compared to wild-type Ret protein in culture (PMID: 22837065).
V804L missense gain of function RET V804L lies within the protein kinase domain of the Ret protein (UniProt.org). V804L confers a gain of function on the Ret protein, as indicated by increased kinase activity, cell transformation (PMID: 9242375), and is considered a gatekeeper mutation due to lack of response to some inhibitors, including cabozantinib and vandetanib (PMID: 27712045). Y
L730V missense unknown RET L730V lies within the protein kinase domain of the Ret protein (UniProt.org). L730V has been demonstrated to confer drug resistance in the context of KIF5B-RET in culture (PMID: 29908090), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2018). Y
C611X missense unknown RET C611X indicates any Ret missense mutation that results in replacement of the cysteine (C) at amino acid 611 by a different amino acid.
K907E missense loss of function - predicted RET K907E lies within the protein kinase domain of the Ret protein (UniProt.org). K907E results in a loss of response to GDNF-regulated apoptosis (PMID: 10921886), and inhibits the function of a concurring activating RET mutation (C634R) in culture (PMID: 9502784) and therefore, is predicted to lead to a loss of Ret protein function.
G736R missense unknown RET G736R lies within the protein kinase domain of the Ret protein (UniProt.org). G736R has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
R873W missense unknown RET R873W lies within the protein kinase domain of the Ret protein (UniProt.org). R873W has been identified in sequencing studies (PMID: 22622578, PMID: 22722839), but has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
E632_L633del deletion gain of function - predicted RET E632_L633del results in the deletion of two amino acids in the cysteine-rich region of the Ret protein from amino acids 632 to 633 (PMID: 9879991). E632_L633del is transforming in cell culture in one study (PMID: 9191060) and therefore, is predicted to lead to a gain of Ret protein function.
E136K missense unknown RET E136K does not lie within any known functional domains of the Ret protein (UniProt.org). E136K has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
L56M missense unknown RET L56M lies within the extracellular domain of the Ret protein (UniProt.org). L56M has not been biochemically characterized, however, it does not affect RET extracellular domain secretion in culture (PMID: 20473317).
C618G missense gain of function - predicted RET C618G lies within the extracellular domain of the Ret protein (UniProt.org). C618G has not been fully biochemically characterized, but is transforming in cell culture (PMID: 9230192), thus is predicted to confer a gain of function on the Ret protein.
R600Q missense unknown RET R600Q lies within the extracellular domain of the Ret protein (UniProt.org). R600Q has been identified in the scientific literature (PMID: 10612852, PMID: 22722839), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
K758M missense loss of function RET K758M lies within the protein kinase domain of the Ret protein (UniProt.org). K754M results in a loss of phosphorylation of Ret and downsream signaling molecules including Erk1/2 and Stat3, decreased colony formation and response to GDNF-regulated apoptosis compared to wild-type Ret protein in culture (PMID: 22837065).
G810A missense unknown RET G810A lies within the protein kinase domain of the Ret protein (UniProt.org). G810A has been demonstrated to confer resistance to Caprelsa (vandetanib) in the context of KIF5B-RET in cell culture (PMID: 27496134), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2018). Y
rearrange unknown unknown RET rearrangement indicates an unspecified rearrangement of the RET gene.
A274G missense unknown RET A274G lies within the extracellular domain of the Ret protein (UniProt.org). A274G has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
V804G missense unknown RET V804G lies within the protein kinase domain of the Ret protein (UniProt.org). V804G has not been characterized individually, however, V804G in combination with C634R results in moderately decreased Ret kinase activity and transformation activity compared to C634R alone in cell culture (PMID: 15184865).
V804M missense gain of function RET V804M lies within the protein kinase domain of the Ret protein (UniProt.org). V804M confers a gain of function on the Ret protein, resulting in increased kinase activity, cell transformation (PMID: 16469774), and is considered a gatekeeper due to lack of response to some inhibitors, including cabozantinib and vandetanib (PMID: 23811235, PMID: 27712045). Y
D631A missense unknown RET D631A lies within the extracellular domain of the Ret protein (UniProt.org). D631A does not result in covalent Ret dimerization and demonstrates low transforming activity in cell culture (PMID: 10049754), but has not been fully biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Oct 2018).
C515W missense gain of function RET C515W lies within the extracellular domain of the Ret protein (UniProt.org). C515W results in increased cell proliferation, S-phase progression, colony formation, cell migration, Ret autophosphorylation, and ERK1/2 and S6 phosphorylation relative to wild-type Ret in culture (PMID: 25725622).
C620Y missense gain of function RET C620Y lies within the extracellular domain of the Ret protein (UniProt.org). C620Y results in constitutive dimerization of Ret, increased Ret kinase activity, and is transforming in cell culture (PMID: 9012462).
V637R missense unknown RET V637R lies within the transmembrane domain of the Ret protein (UniProt.org). V637R has been identified in the scientific literature (PMID: 29657135), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
P1039L missense loss of function - predicted RET P1039L lies within the cytoplasmic domain of the Ret protein (UniProt.org). P1039L results in a loss of response to GDNF-regulated apoptosis in one study (PMID: 10921886) and therefore, is predicted to lead to a loss of Ret protein function.
V637M missense unknown RET V637M lies within the helical domain of the Ret protein (UniProt.org). V637M has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
K666E missense gain of function RET K666E lies within the cytoplasmic domain of the Ret protein (UniProt.org). K666E results in increased Erk1/2 phosphorylation and is transforming in culture (PMID: 21690267).
E505_G506del deletion gain of function RET E505_G506del results in the deletion of 2 amino acids in the protein kinase domain of the Ret protein from amino acids 505 to 506 (UniProt.org). E505_G506del confers a gain of function to the Ret protein as evidenced by increased Mapk pathway activation, phosphorylation of Ret, Akt, and Erk, and increased colony formation in culture (PMID: 26765577).
G691S missense gain of function RET G691S lies within the cytoplasmic domain of the Ret protein (UniProt.org). G691S results in increased Ret phosphorylation and activation of downstream signaling pathways in response to Gdnf, and increased invasion in cultured cells (PMID: 16357163, PMID: 19561646).
C620G missense unknown RET C620G lies within the extracellular domain of the Ret protein (UniProt.org). C620G has been identified in the scientific literature (PMID: 9223675, PMID: 22584707, Endocrine Abstracts 2014 34 P189), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
C611R missense unknown RET C611R lies within the extracellular domain of the Ret protein (UniProt.org). C611R has been identified in the scientific literature (PMID: 22747440, PMID: 23744765, PMID: 25163725), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
positive unknown unknown RET positive indicates the presence of the RET gene, mRNA, and/or protein.
S977R missense unknown RET S977R lies within the protein kinase domain of the Ret protein (UniProt.org). S977R has been identified in sequencing studies (PMID: 26168399), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
R57W missense unknown RET R57W lies within the extracellular domain of the Ret protein (UniProt.org). R57W has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
C618W missense unknown RET C618W lies within the extracellular domain of the Ret protein (UniProt.org). C618W has been identified in the scientific literature (PMID: 17384210, PMID: 14718397), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
C620X missense unknown RET C620X indicates any Ret missense mutation that results in replacement of the cysteine (C) at amino acid 620 by a different amino acid.
D631N missense unknown RET D631N lies within the extracellular domain of the Ret protein (UniProt.org). D631N does not result in covalent Ret dimerization and demonstrates low transforming activity in cell culture (PMID: 10049754), but has not been fully biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Oct 2018).
M1009T missense unknown RET M1009T lies within the protein kinase domain of the Ret protein (UniProt.org). M1009T has been identified in sequencing studies (PMID: 24429398), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
A807V missense unknown RET A807V lies within the protein kinase domain of the Ret protein (UniProt.org). A807V has been demonstrated to confer drug resistance in the context of KIF5B-RET in culture (PMID: 29908090), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2018). Y
C611F missense unknown RET C611F lies within the extracellular domain of the Ret protein (UniProt.org). C611F has been identified in the scientific literature (PMID: 11331212, PMID: 9950371), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
E616Q missense gain of function RET E616Q lies within the extracellular domain of the Ret protein (UniProt.org). E616Q results in increased Ret autophosphorylation and constitutive transcriptional activity in a serum response element-driven luciferase reporter assay in cell culture (PMID: 27704398).
C620R missense gain of function RET C620R lies within the extracellular domain of the Ret protein (PMID: 9230192). C620R results in decreased cell surface Ret expression, but also results in increased Ret and Shc phosphorylation, activation of transcription in a reporter assay, and is transforming in cell culture (PMID: 9879991, PMID: 9230192).
R833C missense gain of function RET R833C lies within the protein kinase domain of the Ret protein (UniProt.org). R833C results in increased Ret autophosphorylation, tumor formation in animal models, and is transforming in cell culture (PMID: 16469774).
V648I missense unknown RET V648I lies within the helical domain of the Ret protein (UniProt.org). V648I has not been biochemically characterized, however, it promotes cell proliferation, but is not transforming in culture (PMID: 21810974).
C515S missense gain of function RET C515S lies within the extracellular domain of the Ret protein (UniProt.org). C515S results in increased cell proliferation, Ret autophosphorylation in vitro and in vivo, and ligand-independent Ret homodimer formation (PMID: 18631007).
C634Y missense gain of function RET C634Y lies within the cysteine-rich region of the Ret protein (PMID: 9230192). C634Y results in formation of covalent Ret homodimers, increased Ret phosphorylation and activation of downstream signaling, resistance to apoptosis, and is transforming in cell culture (PMID: 9230192, PMID: 10919641).
S767R missense loss of function RET S767R lies within the protein kinase domain of the Ret protein (UniProt.org). S767R results in decreased Ret, Erk, and Stat3 phosphorylation, reduced cell migration and colony formation compared to wild-type Ret protein in culture (PMID: 11438491, PMID: 22837065).
V804E missense unknown RET V804E lies within the protein kinase domain of the Ret protein (UniProt.org). V804E has been demonstrated to confer resistance to Ret inhibitors in the context of a RET fusion in culture (PMID: 29657135), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2018). Y
E732K missense unknown RET E732K lies within the protein kinase domain of the Ret protein (UniProt.org). E732K has been demonstrated to confer drug resistance in the context of KIF5B-RET in culture (PMID: 29908090), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2018). Y
F329L missense unknown RET F329L lies within the extracellular domain of the Ret protein (UniProt.org). F329L has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
A883T missense gain of function - predicted RET A883T lies within the protein kinase domain of the Ret protein (UniProt.org). A883T results in increased cell proliferation and foci formation in culture in one study (PMID: 21810974) and therefore, is predicted to lead to a gain of Ret protein function.
C618Y missense gain of function - predicted RET C618Y lies within the extracellular domain of the Ret protein (UniProt.org). C618Y has not been fully biochemically characterized, but is transforming in cell culture (PMID: 9230192), thus is predicted to confer a gain of function on the Ret protein.
D631G missense unknown RET D631G lies within the extracellular domain of the Ret protein (UniProt.org). D631G does not result in covalent Ret dimerization and demonstrates no transforming activity in cell culture (PMID: 10049754), but has not been fully biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Oct 2018).
C609R missense gain of function RET C609R lies within the extracellular domain of the Ret protein (UniProt.org). C609R results in decreased cell surface Ret expression, but also results in increased Ret and Shc phosphorylation, activation of transcription in a reporter assay, and is transforming in cell culture (PMID: 9879991).
M848T missense gain of function - predicted RET M848T lies within the protein kinase domain of the Ret protein (UniProt.org). M848T results in increased cell proliferation and foci formation in culture in one study (PMID: 21810974) and therefore, is predicted to lead to a gain of Ret protein function.
C634_R635insHELC insertion gain of function RET C634_R635insHELC results in the insertion of four amino acids in the extracellular domain of the Ret protein between amino acids 634 and 635 (UniProt.org). C634_R635insHELC results in ligand independent dimerization and constitutive activation of Ret in culture (PMID: 10918602).
C611S missense unknown RET C611S lies within the extracellular domain of the Ret protein (UniProt.org). C611S has been identified in the scientific literature (PMID: 12734540, PMID: 25242331), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
C618S missense gain of function - predicted RET C618S lies within the extracellular domain of the Ret protein (UniProt.org). C618S has not been fully biochemically characterized, but is transforming in cell culture (PMID: 9230192), thus is predicted to confer a gain of function on the Ret protein.
L923I missense unknown RET L923I lies within the protein kinase domain of the Ret protein (UniProt.org). L923I has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
D631_R635delinsG indel unknown RET D631_R635delinsG results in a deletion of five amino acids in the extracellular domain of the Ret protein from amino acids 631 to 635, combined with the insertion of a glycine (G) at the same site (UniProt.org). D631_R635delinsG has been identified in the scientific literature (PMID: 29657135), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
R912L missense unknown RET R912L lies within the protein kinase domain of the Ret protein (UniProt.org). R912L has been identified in sequencing studies (PMID: 28179366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
E1006D missense unknown RET E1006D lies within the protein kinase domain of the Ret protein (UniProt.org). E1006D has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
G446R missense unknown RET G446R lies within the extracellular domain of the Ret protein (UniProt.org). G446R has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
S891A missense gain of function RET S891A lies within the protein kinase domain of the Ret protein (UniProt.org). S891A results in constitutive phosphorylation of Ret and downstream activation of Stat3 signaling through Src, Jak1, and Jak2-dependent pathways in cell culture (PMID: 15753368).
C609X missense unknown RET C609X indicates any Ret missense mutation that results in replacement of the cysteine (C) at amino acid 609 by a different amino acid.
M918T missense gain of function RET M918T lies within the protein kinase domain of the Ret protein (Uniprot.org). M918T results in ligand-independent autophosphorylation of Ret and increased substrate binding, is transforming (PMID: 17108110), and confers drug resistance in the context of KIF5B-RET in culture (PMID: 29908090). Y
R721W missense unknown RET R721W lies within the cytoplasmic domain of the Ret protein (UniProt.org). R721W has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
D771N missense loss of function RET D771N lies within the protein kinase domain of the Ret protein (UniProt.org). D771N results in decreased phosphorylation of Ret and downsream signaling molecules including Erk1/2 and Stat3, decreased migration, colony formation, and response to GDNF-regulated apoptosis compared to wild-type Ret protein in culture (PMID: 22837065).
T278N missense unknown RET T278N lies within the extracellular domain of the Ret protein (UniProt.org). T278N has been identified in sequencing studies (PMID: 24845513, PMID: 20668451), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
C634F missense gain of function - predicted RET C634F lies within the cysteine-rich region of the Ret protein (PMID: 9879991). C634F has not been fully biochemically characterized, but is transforming in cell culture (PMID: 9230192), thus is predicted to confer a gain of function on the Ret protein.
V804X missense unknown RET V804X indicates any Ret missense mutation that results in replacement of the valine (V) at amino acid 804 by a different amino acid.
P1070S missense unknown RET P1070S lies within the cytoplasmic domain of the Ret protein (UniProt.org). P1070S has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
C630S missense unknown RET C630S lies within the cysteine-rich region of the Ret protein (PMID: 9879991). C630S has been identified in sequencing studies (PMID: 15523405), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Oct 2018).
R231H missense loss of function - predicted RET R231H lies within the Cadherin domain of the Ret protein (UniProt.org). R231H results in a loss of response to GDNF-regulated apoptosis (PMID: 10921886), and inhibits the expression and function of a concurring activating RET mutation (C634R) in culture (PMID: 9502784) and therefore, is predicted to lead to a loss of Ret protein function.
A883F missense gain of function RET A883F lies within the protein kinase domain of the Ret protein (UniProt.org). A883F confers a gain of function to the Ret protein as demonstrated by increased Ret kinase activity (PMID: 24561444) and is transforming in cell culture (PMID: 10445857, PMID: 10679286).
C620S missense gain of function - predicted RET C620S lies within the extracellular domain of the Ret protein (UniProt.org). C620S has not been fully biochemically characterized, but is transforming in cell culture (PMID: 9230192), thus is predicted to confer a gain of function on the Ret protein.
F185L missense unknown RET F185L lies within the cadherin domain of the Ret protein (UniProt.org). F185L has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
F893L missense loss of function RET F893L lies within the protein kinase domain of the Ret protein (UniProt.org). F893L results in a loss of ligand-dependent phosphorylation of Ret and downstream signaling molecules including Erk, Akt, and PLCgamma, is not transforming in culture, and abolishes the activity of a concurring activating IDH1 mutation (C634R) in culture (PMID: 11438491, PMID; 22837065).
Y606C missense gain of function RET Y606C lies within the extracellular domain of the Ret protein (UniProt.org). Y606C results in ligand independent dimerization and constitutive phosphorylation of Ret, and increased Erk2 phosphorylation in culture (PMID: 18248647).
R912P missense unknown RET R912P lies within the protein kinase domain of the Ret protein (UniProt.org). R912P has been identified in the scientific literature (PMID: 15240641), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
C634L missense gain of function RET C634L lies within the cysteine-rich region of the Ret protein (PMID: 9879991). C634L results in ligand-independent dimerization of Ret and increased cell proliferation in culture (PMID: 27841748).
M918V missense no effect - predicted RET M918V lies within the protein kinase domain of the Ret protein (UniProt.org). M918V results in cell proliferation and foci formation to similar levels of wild-type Ret protein in culture in one study (PMID: 21810974) and therefore, is predicted to have no effect on Ret protein function.
Y791X missense unknown RET Y791X indicates any Ret missense mutation that results in replacement of the tyrosine (Y) at amino acid 791 by a different amino acid.
C630R missense gain of function RET C630R lies within the cysteine-rich region of the Ret protein (PMID: 9879991). C630R results in constitutive Ret phosphorylation and increased Ret kinase activity, formation of covalent Ret homodimers, and is transforming in cell culture (PMID: 9879991, PMID: 9230192).
W85* nonsense loss of function - predicted RET W85* results in a premature truncation of the Ret protein at amino acid 85 of 1114 (UniProt.org). Due to the loss of all known functional domains (UniProt.org), W85* is predicted to lead to a loss of Ret protein function.
fusion fusion unknown RET fusion indicates a fusion of the RET gene, but the fusion partner is unknown.
C609Y missense gain of function RET C609Y lies within the extracellular domain of the Ret protein (UniProt.org). C609Y results in constitutive activation of Ret, increased resistance to apoptosis, transformation of cultured cells, and enhanced tumor growth in mouse models (PMID: 16715139, PMID: 9230192).
R972G missense loss of function RET R972G lies within the protein kinase domain of the Ret protein (UniProt.org). R972G results in decreased GDNF-dependent phosphorylation of Ret and downstream signaling molecules including Shc, PLCgamma, and Erk1/2 compared to wild-type Ret protein, and inhibits the activity of a concurring activation mutation (C634R) in culture (PMID: 11438491).
V915_K916insVHR insertion unknown RET V915_K916insVHR results in the insertion of three amino acids in the protein kinase domain of the Ret protein between amino acids 915 and 916 (UniProt.org). V915_K916insVHR has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
act mut unknown gain of function RET act mut indicates that this variant results in a gain of function in the Ret protein. However the specific amino acid change has not been identified.
C618X missense unknown RET C618X indicates any Ret missense mutation that results in replacement of the cysteine (C) at amino acid 618 by a different amino acid.
E805K missense gain of function - predicted RET E805K lies within the protein kinase domain of the Ret protein (UniProt.org). E805K demonstrates weak transforming ability in culture in one study (PMID: 17047083) and therefore, is predicted to lead to a gain of Ret protein function.
R67H missense unknown RET R67H lies within the extracellular domain of the Ret protein (UniProt.org). R67H has been identified in the scientific literature (PMID: 21655256), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
E884K missense unknown RET E884K lies within the protein kinase domain of the Ret protein (UniProt.org). E884K has been identified in the scientific literature (PMID: 10622534, PMID: 19029224, PMID: 28351340), but has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
M918X missense unknown RET M918X indicates any Ret missense mutation that results in replacement of the methionine (M) at amino acid 918 by a different amino acid.
A756D missense unknown RET A756D lies within the protein kinase domain of the Ret protein (UniProt.org). A756D has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
C609G missense unknown RET C609G lies within the extracellular domain of the Ret protein (UniProt.org). C609G has been identified in the scientific literature (PMID: 8626834, PMID: 18062802, PMID: 24699901), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
C634S missense gain of function RET C634S lies within the cysteine-rich region of the Ret protein (PMID: 9879991). C634S confers a gain of function on the Ret protein as demonstrated by constitutive phosphorylation of Mapk and transformation of cultured cells (PMID: 15277225, PMID: 9230192).
S904F missense unknown RET S904F lies within the protein kinase domain of the Ret protein (UniProt.org). S904F increases foci formation but does not have significant effect on cell proliferation in culture in one study (PMID: 21810974) and therefore, its effect on Ret protein function is unknown.
Q781R missense unknown RET Q781R lies within the protein kinase domain of the Ret protein (UniProt.org). Q781R has been identified in the scientific literature (PMID: 21422198, PMID: 23240926), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
R1013del deletion unknown RET R1013del results in the deletion of one amino acid in the protein kinase domain of the Ret protein at amino acid 1013 (UniProt.org). R1013del has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Oct 2018).
R897Q missense loss of function RET R897Q lies within the protein kinase domain of the Ret protein (UniProt.org). R897Q results in a loss of ligand-dependent phosphorylation of Ret and downstream signaling molecules including Erk, Akt, and PLCgamma, is not transforming in culture, and abolishes the activity of a concurring activating IDH1 mutation (C634R) in culture (PMID: 11438491).
C630X missense unknown RET C630X indicates any Ret missense mutation that results in replacement of the cysteine (C) at amino acid 630 by a different amino acid.
G601W missense unknown RET G601W lies within the extracellular domain of the Ret protein (UniProt.org). G601W has been identified in sequencing studies (PMID: 22980975), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
wild-type none no effect Wild-type RET indicates that no mutation has been detected within the RET gene.
Y791F missense gain of function RET Y791F lies within the protein kinase domain of the Ret protein (UniProt.org). Y791F confers a gain of function on the Ret protein, resulting in ligand independent kinase activity and activation of Stat3 signaling through Src, Jak1, and Jak2-dependent pathways in cell culture (PMID: 15753368).
Y806F missense unknown RET Y806F lies within the protein kinase domain of the Ret protein (UniProt.org). Y806F has not been biochemically characterized, however, does not alter drug sensitivity in the context of other RET activating mutations (PMID: 19029224).
L730I missense unknown RET L730I lies within the protein kinase domain of the Ret protein (UniProt.org). L730I has been demonstrated to confer drug resistance in the context of KIF5B-RET in culture (PMID: 29908090), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2018). Y
I852M missense gain of function RET I852M lies within the protein kinase domain of the Ret protein (UniProt.org). I852M confers a gain of function on the Ret protein as demonstrated by constitutive activation of Ret, increased cell proliferation, elevated migration activity, and modest transforming ability in culture (PMID: 21711375).
V292M missense gain of function RET V292M lies within the cadherin-like domain 3 of the Ret protein (PMID: 20039896). V292M results in Ret autophosphorylation, increased phosphorylation of Mapk, Mek, and Shc, increased cell proliferation, but has low transforming activity in culture (PMID: 20039896).
C634X missense unknown RET C634X indicates any Ret missense mutation that results in replacement of the cysteine (C) at amino acid 634 by a different amino acid.
L629P missense unknown RET L629P lies within the extracellular domain of the Ret protein (UniProt.org). L629P has been identified in the scientific literature (PMID: 29657135), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
E768X missense unknown RET E768X indicates any Ret missense mutation that results in replacement of the glutamic acid (E) at amino acid 768 by a different amino acid.
E762Q missense loss of function RET E762Q lies within the protein kinase domain of the Ret protein (UniProt.org). E762Q results in decreased GDNF-dependent phosphorylation of Ret and downstream signaling molecules including Shc, PLCgamma, and Erk1/2 compared to wild-type Ret protein, and inhibits the activity of a concurring activation mutation (C634R) in culture (PMID: 11438491).
C630Y missense gain of function - predicted RET C630Y lies within the extracellular domain of the Ret protein (UniProt.org). C630Y is transforming in culture in one study (PMID: 10049754) and therefore, is predicted to lead to a gain of Ret protein function.
V125F missense unknown RET V125F lies within the extracellular domain of the Ret protein (UniProt.org). V125F has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
mutant unknown unknown RET mutant indicates and unspecified mutation in the RET gene.
M980T missense loss of function RET M980T lies within the protein kinase domain of the Ret protein (UniProt.org). M980T results in decreased ligand-dependent phosphorylation of Ret and downstream signaling molecules including PLCgamma, Shc, and Erk in culture (PMID: 11438491).
C611Y missense gain of function RET C611Y lies within the extracellular domain of the Ret protein (UniProt.org). C611Y confers a gain of function on the Ret protein as indicated by dimerization of Ret and transformation of cultured cells (PMID: 9230192).
D631Y missense gain of function RET D631Y lies within the extracellular domain of the Ret protein (UniProt.org). D631Y confers a gain of function on the Ret protein as demonstrated by induction of covalent Ret dimerization and phosphorylation, and transformation of cultured cells (PMID: 10049754).
C634W missense gain of function RET C634W lies within the extracellular domain of the Ret protein (UniProt.org). C634W results in ligand independent dimerization and constitutive activation of Ret, and is transforming in culture (PMID: 10918602, PMID: 9230192).
C609W missense unknown RET C609W lies within the extracellular domain of the Ret protein (UniProt.org). C609W has dual effects on Ret protein function, it reduces cell surface Ret expression, results in a loss of response to GDNF-regulated apoptosis, but also induces Ret dimerization, leads to increased phosphorylation of Shc, and transformation of cultured cells (PMID: 9502784, PMID: 10921886).
R418* nonsense loss of function - predicted RET R418* results in a premature truncation of the Ret protein at amino acid 418 of 1114 (UniProt.org). Due to the loss of the protein kinase domain (UniProt.org), R418* is predicted to lead to a loss of Ret protein function.
R959W missense unknown RET R959W lies within the protein kinase domain of the Ret protein (UniProt.org). R959W has been identified in sequencing studies (PMID: 24728327), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
amp none unknown RET amp indicates an increased number of copies of the RET gene. However, the mechanism causing the increase is unspecified.
S904C missense unknown RET S904C lies within the protein kinase domain of the Ret protein (UniProt.org). S904C has been identified in the scientific literature (PMID: 11788682, PMID: 19169500), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
T742M missense unknown RET T742M lies within the protein kinase domain of the Ret protein (UniProt.org). T742M has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
D898V missense unknown RET D898V lies within the protein kinase domain of the Ret protein (UniProt.org). D898V has been identified in the scientific literature (PMID: 23526464), but has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
R873Q missense loss of function RET R873Q lies within the protein kinase domain of the Ret protein (UniProt.org). R873Q results in a loss of ligand-dependent phosphorylation of Ret and downstream signaling molecules including Erk, Akt, and PLCgamma, is not transforming in culture, and abolishes the activity of a concurring activating IDH1 mutation (C634R) in culture (PMID: 11438491, PMID: 22837065).
C634G missense gain of function - predicted RET C634G lies within the cysteine-rich region of the Ret protein (PMID: 9879991). C634G has not been fully biochemically characterized, but is transforming in cell culture (PMID: 9230192), thus is predicted to confer a gain of function on the Ret protein.
I788N missense unknown RET I788N lies within the protein kinase domain of the Ret protein (UniProt.org). I788N has been associated with Ret inhibitor resistance in the context of Ret fusions (PMID: 28615362), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2018). Y
Molecular Profile Protein Effect Treatment Approaches
RET C620F unknown
RET R813Q loss of function
RET C611W gain of function - predicted
RET T1038A unknown
RET L790F unknown
RET L923H unknown
RET D631_L633delinsE unknown
RET R77L unknown
RET C634R RET Y806E
RET Y806E unknown
RET Y806N unknown
RET A883X unknown
RET F998V unknown
RET C609S gain of function - predicted RET Inhibitor
RET S891X unknown
RET S649L gain of function RET Inhibitor
RET V871I unknown
RET E632_T636delinsSS unknown
RET R982C no effect - predicted
RET E921K loss of function
RET over exp no effect
RET R912Q loss of function
RET S936F unknown
RET L517V unknown
RET T278S unknown
RET T338I unknown
RET C609F unknown
RET C618R gain of function RET Inhibitor
RET C634R RET V804G
RET C634R RET Y806F
RET C634R gain of function RET Inhibitor
RET C634R RET V804M
RET C634R RET Y806C
RET P273L unknown
RET E623_L633del unknown
RET S765P loss of function
RET M1064T unknown
RET L790X unknown
RET A919V unknown
RET G533C gain of function RET Inhibitor
RET A1105V no effect - predicted
RET V804M + RET Y806C
RET Y806C gain of function - predicted
RET E768D gain of function RET Inhibitor
RET E632K unknown
RET C611G unknown
RET C630F gain of function RET Inhibitor
RET C620W unknown
RET G810S unknown
RET S891L unknown
RET V738A unknown
RET F612_C620del unknown
RET A756V unknown
RET E623K unknown
RET R770Q unknown
RET P973L loss of function - predicted
RET V253E unknown
RET L633_C634dup gain of function RET Inhibitor
RET C630G unknown RET Inhibitor
RET R77H unknown
RET E734K loss of function
RET V804L gain of function RET Inhibitor
RET L730V unknown
RET C611X unknown
RET K907E loss of function - predicted
RET G736R unknown
RET R873W unknown
RET E632_L633del gain of function - predicted RET Inhibitor
RET E136K unknown
RET L56M unknown
RET C618G gain of function - predicted
RET R600Q unknown
RET K758M loss of function
RET G810A unknown
RET rearrange unknown
RET A274G unknown
RET V804G unknown
RET V804M + RET E805K
RET V804M + RET S904C
RET V804M gain of function RET Inhibitor
RET M918T RET V804M
RET D631A unknown
RET C515W gain of function RET Inhibitor
RET C620Y gain of function RET Inhibitor
RET D631_R635delinsG RET L629P RET V637R
RET V637R unknown
RET P1039L loss of function - predicted
RET V637M unknown
RET K666E gain of function RET Inhibitor
RET E505_G506del gain of function RET Inhibitor
RET G691S gain of function
RET C620G unknown
RET C611R unknown
RET positive unknown
RET S977R unknown
RET R57W unknown
RET C618W unknown
RET C620X unknown
RET D631N unknown
RET M1009T unknown
EGFR R521K FGFR2 M186T KDR Q472H KDR V297I RET M1009T
RET A807V unknown
RET C611F unknown
RET E616Q gain of function
RET C620R gain of function
RET R833C gain of function RET Inhibitor
RET V648I unknown
RET C515S gain of function RET Inhibitor
RET C634Y gain of function RET Inhibitor
RET S767R loss of function
RET V804E unknown
RET E732K unknown
RET F329L unknown
RET A883T gain of function - predicted RET Inhibitor
RET C618Y gain of function - predicted
RET D631G unknown
RET C609R gain of function
RET M848T gain of function - predicted RET Inhibitor
RET C634_R635insHELC gain of function RET Inhibitor
RET C611S unknown
RET C618S gain of function - predicted
RET L923I unknown
RET D631_R635delinsG unknown
RET R912L unknown
RET E1006D unknown
RET G446R unknown
RET S891A gain of function RET Inhibitor
RET C609X unknown
ATM L804fs ATM S978fs RET M918T
RET M918T gain of function RET Inhibitor
RET R721W unknown
RET D771N loss of function
RET T278N unknown
RET C634F gain of function - predicted RET Inhibitor
RET V804X unknown
RET P1070S unknown
RET C630S unknown RET Inhibitor
RET R231H loss of function - predicted
RET A883F gain of function RET Inhibitor
RET C620S gain of function - predicted
RET F185L unknown
RET F893L loss of function
RET Y606C gain of function RET Inhibitor
RET R912P unknown
RET C634L gain of function RET Inhibitor
RET M918V no effect - predicted RET Inhibitor
RET Y791X unknown
RET C630R gain of function RET Inhibitor
RET W85* loss of function - predicted
RET fusion unknown
RET C609Y gain of function RET Inhibitor
RET R972G loss of function
RET V915_K916insVHR unknown
RET act mut gain of function RET Inhibitor
RET C618X unknown
RET E805K gain of function - predicted RET Inhibitor
RET R67H unknown
RET E884K unknown
RET M918X unknown
RET A756D unknown
RET C609G unknown
RET C634S gain of function RET Inhibitor
RET S904F unknown RET Inhibitor
RET Q781R unknown
RET R1013del unknown
RET R897Q loss of function
RET C630X unknown
RET G601W unknown
RET wild-type no effect
RET Y791F gain of function RET Inhibitor
RET Y806F unknown
RET L730I unknown
RET I852M gain of function RET Inhibitor
RET V292M gain of function RET Inhibitor
RET C634X unknown
RET L629P unknown
RET E768X unknown
RET E762Q loss of function
RET C630Y gain of function - predicted RET Inhibitor
RET V125F unknown
RET mutant unknown
RET M980T loss of function
RET C611Y gain of function RET Inhibitor
RET D631Y gain of function RET Inhibitor
KDR pos RET C634W
RET C634W gain of function RET Inhibitor
RET C609W unknown
RET R418* loss of function - predicted
RET R959W unknown
ROS1 fusion ERBB2 amp FGFR3 amp RET amp
RET amp unknown RET Inhibitor
RET S904C unknown
RET T742M unknown
RET D898V unknown
RET R873Q loss of function
RET C634G gain of function - predicted RET Inhibitor
RET I788N unknown
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET L790F Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET L790F in culture (PMID: 23526464). 23526464
RET L790F Advanced Solid Tumor sensitive Vandetanib Preclinical Actionable In a preclinical study, Caprelsa (vandetanib) inhibited Ret autophosphorylation in transformed cells expressing RET L790F in culture (PMID: 15184865). 15184865
RET C634R RET Y806E Advanced Solid Tumor resistant Vandetanib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells co-expressing RET C634R and RET Y806E were resistant to treatment with Caprelsa (vandetanib) in culture (PMID: 19029224). 19029224
RET A883X thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET A883X mutations result in multiple endocrine neoplasia, type 2B (MEN 2B), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET S891X thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET S891X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with increased risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET over exp breast cancer sensitive Y078-DM1 Preclinical - Cell line xenograft Actionable In a preclinical study, Y078-DM1 induced cytotoxicity in a human breast cancer cell line with high levels of RET expression in culture and inhibited tumor growth in xenograft models (PMID: 26240273). 26240273
RET C618R thyroid medullary carcinoma predicted - sensitive Sorafenib Phase II Actionable In a Phase II trial, Nexavar (sorafenib) treatment resulted in stable disease in one patient with medullary thyroid carcinoma harboring RET C618R (PMID: 20368568). 20368568
RET C634R RET V804G Advanced Solid Tumor sensitive Vandetanib Preclinical Actionable In a preclinical study, transformed cell lines expressing Ret protein carrying both C634R and V804G mutations were more sensitive to Vandetanib induced inhibition of Ret activity than cells expressing Ret C634R alone in culture (PMID: 15184865). 15184865
RET C634R RET Y806F Advanced Solid Tumor predicted - sensitive Vandetanib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells co-expressing RET C634R and RET Y806F in culture demonstrated inhibition of Ret phosphorylation and activity in kinase assays when treated with Caprelsa (vandetanib) (PMID: 19029224). 19029224
RET C634R Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, transformed human cell lines expressing RET C634R demonstrated sensitivity to Iclusig (ponatinib) (PMID: 23811235). 23811235
RET C634R Advanced Solid Tumor sensitive Pz-1 Preclinical - Cell line xenograft Actionable In a preclinical study, Pz-1 inhibited Ret signaling in transformed cells over expressing RET C634R and inhibited tumor growth in cell line xenografts models (PMID: 26126987). 26126987
RET C634R Advanced Solid Tumor sensitive Vandetanib Preclinical Actionable In a preclinical study, Caprelsa (vandetanib) inhibited RET phosphorylation and decreased growth of transformed cells expressing RET C634R in culture (PMID: 15184865). 15184865
RET C634R Advanced Solid Tumor sensitive Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and decreased growth of cells expressing RET C634R in culture (PMID: 17664273). 17664273
RET C634R Advanced Solid Tumor sensitive Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) inhibited RET kinase activity and proliferation in transformed cells expressing RET C634R in culture (PMID: 16507829). 16507829
RET C634R thyroid medullary carcinoma predicted - sensitive Sorafenib Phase II Actionable In a Phase II trial, Nexavar (sorafenib) treatment resulted in partial response in 50% (1/2) and stable disease in 50% (1/2) of patients with medullary thyroid carcinoma harboring RET C634R (PMID: 20368568). 20368568
RET C634R RET V804M Advanced Solid Tumor resistant Vandetanib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells co-expressing RET C634R and RET V804M were resistant to treatment with Caprelsa (vandetanib) in culture (PMID: 19029224). 19029224
RET C634R RET Y806C Advanced Solid Tumor resistant Vandetanib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells co-expressing RET C634R and RET Y806C were resistant to treatment with Caprelsa (vandetanib) in culture (PMID: 19029224). 19029224
RET L790X thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET L790X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with increased risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET V804M + RET Y806C thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Compound germline RET V840M and Y806C mutations result in multiple endocrine neoplasia, type 2B (MEN 2B), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET Y806C Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET Y806C in culture (PMID: 23526464). 23526464
RET E768D Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET E768D in culture (PMID: 23526464). 23526464
RET E768D Advanced Solid Tumor sensitive Vandetanib Preclinical Actionable In a preclinical study, Caprelsa (vandetanib) inhibited Ret autophosphorylation in transformed cells expressing RET E768D in culture (PMID: 15184865). 15184865
RET V804L Advanced Solid Tumor predicted - sensitive Pz-1 Preclinical Actionable In a preclinical study, Pz-1 inhibited Ret phosphorylation in transformed cells expressing RET V804L (PMID: 26126987). 26126987
RET V804L Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, transformed human cell lines expressing RET V804L demonstrated sensitivity to Iclusig (ponatinib) (PMID: 23811235). 23811235
RET V804L Advanced Solid Tumor resistant Vandetanib Preclinical Actionable In a preclinical study, transformed cells expressing RET V804L demonstrated resistance to growth inhibition by Caprelsa (vandetanib) in culture (PMID: 15184865). 15184865
RET C611X thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET C611X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET rearrange non-small cell lung carcinoma sensitive Sunitinib Clinical Study Actionable In a clinical study, analysis of patients with RET-rearranged non-small cell lung cancer treated with RET inhibitors demonstrated a response rate of 18% (2/9, all partial responses), and stable disease in 33% (3/9) of patients following Sutent (sunitinib) treatment (PMID: 28447912). 28447912
RET rearrange lung cancer sensitive Cabozantinib Phase II Actionable In a Phase II clinical trial, treatment with Cometriq (cabozantinib) resulted in an overall response rate of 28% (7/25) in patients with RET-rearranged lung cancer (PMID: 27825636). 27825636
RET rearrange non-small cell lung carcinoma sensitive CEP-32496 Clinical Study Actionable In a clinical case study, a patient with non-small cell lung cancer harboring a RET rearrangement demonstrated a sustained partial response following treatment with RXDX-105 (CEP-32496) on a Phase Ib clinical trial (PMID: 28011461). 28011461
RET rearrange non-small cell lung carcinoma sensitive Cabozantinib Guideline Actionable Cometriq (cabozantinib) is in guidelines for non-small cell lung cancer patients with RET rearrangements (NCCN.org). detail...
RET rearrange non-small cell lung carcinoma sensitive Cabozantinib Clinical Study Actionable In a clinical study, analysis of patients with RET-rearranged non-small cell lung cancer treated with RET inhibitors demonstrated a response rate of 37% (7/19), with complete response in 5% (1/19) and partial response in 32% (6/19) of patients, and stable disease in 26% (5/19) of patients following Cometriq (cabozantinib) treatment (PMID: 28447912). 28447912
RET rearrange papillary thyroid carcinoma sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) decreased proliferation of papillary thyroid carcinoma cells harboring the RET/PTC1 rearrangement in culture (PMID: 23526464). 23526464
RET rearrange papillary thyroid carcinoma sensitive Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and activation of downstream signaling, and decreased growth of papillary thyroid carcinoma cells harboring the RET/PTC1 oncogene in culture (PMID: 17664273). 17664273
RET rearrange non-small cell lung carcinoma predicted - sensitive Alectinib Clinical Study Actionable In a clinical study, Alecensa (alectinib) treatment resulted in objective radiographic response in 50% (2/4) and stable disease in 25% (1/4) of non-small cell lung carcinoma patients harboring RET rearrangement (PMID: 27544060). 27544060
RET rearrange Advanced Solid Tumor sensitive CEP-32496 Preclinical - Pdx Actionable In a preclinical study, CEP-32496 (RXDX-105) induced tumor regression in patient-derived xenograft models of several advanced solid tumor type with RET rearrangements (2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; Abstract A174). detail...
RET rearrange non-small cell lung carcinoma sensitive Vandetanib Clinical Study Actionable In a clinical study, analysis of patients with RET-rearranged non-small cell lung cancer treated with RET inhibitors demonstrated a response rate of 18% (2/11, all partial responses) and stable disease in 27% (3/11) of patients following Caprelsa (vandetanib) treatment (PMID: 28447912). 28447912
RET rearrange non-small cell lung carcinoma sensitive Vandetanib Guideline Actionable Caprelsa (vandetanib) is in guidelines for non-small cell lung cancer patients with RET rearrangements (NCCN.org). detail...
RET V804M + RET E805K thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Compound germline RET V840M and E805K mutations result in multiple endocrine neoplasia, type 2B (MEN 2B), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET V804M + RET S904C thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Compound germline RET V840M and S904C mutations result in multiple endocrine neoplasia, type 2B (MEN 2B), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET V804M Advanced Solid Tumor sensitive Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and decreased growth of transformed cells expressing RET V804M in culture (PMID: 16507829). 16507829
RET V804M Advanced Solid Tumor predicted - sensitive Pz-1 Preclinical Actionable In a preclinical study, Pz-1 inhibited Ret phosphorylation in transformed cells expressing RET V804M (PMID: 26126987). 26126987
RET V804M thyroid medullary carcinoma sensitive LOXO-292 Phase I Actionable In a Phase I trial, LOXO-292 treatment resulted in partial response in a thyroid medullary cancer patientharboring RET V804M (J Clin Oncol 36, 2018 (suppl; abstr 102); NCT03157128). detail...
RET V804M Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, transformed human cell lines expressing RET V804M demonstrated sensitivity to Iclusig (ponatinib) (PMID: 23811235). 23811235
RET V804M Advanced Solid Tumor resistant Vandetanib Preclinical Actionable In a preclinical study, transformed cells expressing RET V804M demonstrated resistance to growth inhibition by Caprelsa (vandetanib) in culture (PMID: 15184865). 15184865
RET M918T RET V804M thyroid medullary carcinoma sensitive LOXO-292 Clinical Study Actionable In a clinical case study, a patient with thyroid medullary cancer harboring RET M918T and RET V804M demonstrated an initial response to LOXO-292, which included a decrease in allelic fraction of RET M918T and RET V804M over 8 weeks and a radiographic response of nearly 54% post 6.9 months of treatment (PMID: 29912274; NCT03157128). 29912274
RET M918T RET V804M lung adenocarcinoma resistant Alectinib Clinical Study Actionable In a clinical case study, a patient with lung adenocarcinoma initially treated with chemotherapy and immunotherapy was found to harbor KIF5B-RET, and was then treated with Alecensa (alectinib), which resulted in an intracranial response, but eventually led to further progression (PMID: 29912274; NCT03157128). 29912274
RET M918T RET V804M thyroid medullary carcinoma resistant Vandetanib + Everolimus Clinical Study Actionable In a clinical case study, a patient with thyroid medullary carcinoma harboring RET M918T progressed on multiple therapies, including Nexavar (sorafenib), Caprelsa (vandetanib), Cometriq (cabozantinib), MGCD-516 (sitravatinib), and RXDX-105 (CEP-32496), and upon progression with the combination therapy, Vandetanib and Afinitor (everolimus), cell-free DNA testing revealed RET M918T and acquisition of a secondary drug resistant mutation, RET V804M (PMID: 29912274; NCT03157128). 29912274
RET D631_R635delinsG RET L629P RET V637R thyroid medullary carcinoma predicted - sensitive BLU-667 Phase I Actionable In a Phase I trial, a patient with medullary thryoid cancer harboring RET D631_R635delinsG, L629P, and V637R demonstrated a partial response, with maximal tumor reduction of 47% at 10 months, following treatment with BLU-667 (PMID: 29657135; NCT03037385). 29657135
RET G691S Advanced Solid Tumor sensitive Dovitinib Phase I Actionable In a Phase I clinical trial, two patients with germline RET G691S mutations demonstrated sensitivity to Dovitinib (TKI258) treatment (PMID: 25103625). 25103625
RET positive thyroid medullary carcinoma sensitive Y078-DM4 Preclinical Actionable In a preclinical study, Y078-DM4 induced cytotoxicity in a RET-expressing medullary thyroid cell line in culture (PMID: 26240273). 26240273
RET positive breast cancer sensitive Y078-DM4 Preclinical - Cell line xenograft Actionable In a preclinical study, Y078-DM4 induced cytotoxicity in RET-expressing human breast cancer cell lines in culture and inhibited tumor growth in xenograft models (PMID: 26240273). 26240273
RET C620X thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET C620X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...
EGFR R521K FGFR2 M186T KDR Q472H KDR V297I RET M1009T olfactory neuroblastoma sensitive Cetuximab + Sunitinib Clinical Study Actionable In clinical case study, a patient with olfactory neuroblastoma harboring EGFR R521K, FGFR2 M186T, KDR Q472H, KDR V297I, and RET M1009T demonstrated sensitivity to the combination of Sutent (sunitinib) and Erbitux (cetuximab), resulting in a complete response (PMID: 27149458). 27149458
RET C620R thyroid medullary carcinoma sensitive Everolimus Phase II Actionable In a Phase II clinical trial, Afinitor (everolimus) treatment resulted in stable disease of 116 weeks in a MEN2A patient with medullary thyroid cancer carrying a RET C620R mutation (PMID: 26294908). 26294908
RET C634Y Advanced Solid Tumor sensitive ALW-II-41-27 Preclinical - Cell culture Actionable In a preclinical study, ALW-II-41-27 inhibited RET phosphorylation and downstream signaling, reduced proliferation of transformed cells expressing RET C634Y in culture (PMID: 26046350). 26046350
RET C634Y Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited proliferation of transformed cells harboring RET C634Y in culture (PMID: 23526464). 23526464
RET C634Y thyroid medullary carcinoma predicted - sensitive Sorafenib Phase II Actionable In a Phase II trial, Nexavar (sorafenib) treatment resulted in stable disease in one patient with medullary thyroid carcinoma harboring RET C634Y (PMID: 20368568). 20368568
RET C634Y Advanced Solid Tumor sensitive HG-6-63-01 Preclinical Actionable In a preclinical study, HG-6-63-01 inhibited RET phosphorylation and downstream signaling and reduced proliferation of transformed cells expressing RET C634Y in culture (PMID: 26046350). 26046350
RET C634Y Advanced Solid Tumor sensitive XMD15-44 Preclinical Actionable In a preclinical study, XMD15-44 inhibited RET phosphorylation and downstream signaling and reduced proliferation of transformed cells expressing RET C634Y in culture (PMID: 26046350). 26046350
RET S891A Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET S891A in culture (PMID: 23526464). 23526464
RET S891A Advanced Solid Tumor sensitive Vandetanib Preclinical Actionable In a preclinical study, Caprelsa (vandetanib) inhibited Ret autophosphorylation in transformed cells expressing RET S891A in culture (PMID: 15184865). 15184865
RET S891A Advanced Solid Tumor sensitive Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation in cells expressing RET S891A in culture (PMID: 17664273). 17664273
RET C609X thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET C609X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with increased risk of developing thyroid medullary carcinoma (NCCN.org). detail...
ATM L804fs ATM S978fs RET M918T thyroid medullary carcinoma predicted - sensitive Vandetanib + Everolimus Clinical Study Actionable In a clinical case study, addition of Afinitor (everolimus) to Caprelsa (vandetanib) treatment resulted in significant tumor reduction in a medullary thyroid carcinoma patient harboring ATM L804fs*4, ATM S978fs*12, and RET M918T, that achieved prolonged stable disease on Caprelsa (vandetanib) treatment alone (PMID: 27683183). 27683183
RET M918T Advanced Solid Tumor sensitive XMD15-44 Preclinical Actionable In a preclinical study, XMD15-44 inhibited RET phosphorylation and downstream signaling and reduced proliferation of transformed cells expressing RET M918T in culture (PMID: 26046350). 26046350
RET M918T Advanced Solid Tumor sensitive Vandetanib Preclinical Actionable In a preclinical study, Caprelsa (vandetanib) inhibited Ret autophosphorylation and transforming activity in cells expressing RET M918T in culture (PMID: 15184865). 15184865
RET M918T Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET M918T in culture (PMID: 23526464). 23526464
RET M918T thyroid medullary carcinoma predicted - sensitive BLU-667 Phase I Actionable In a Phase I trial, a patient with sporadic medullary thryoid cancer harboring RET M918T demonstrated a partial response, with maximal tumor reduction of 47% following treatment with BLU-667 (PMID: 29657135; NCT03037385). 29657135
RET M918T Advanced Solid Tumor sensitive LOXO-292 Preclinical - Cell culture Actionable In a preclinical study, cells expressing RET M918T were sensitive to treatment with LOXO-292 in culture, demonstrating decreased cell proliferation (PMID: 29912274). 29912274
RET M918T thyroid carcinoma sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited RET signaling and decreased proliferation of thyroid carcinoma cells harboring a RET M918T mutation in culture (PMID: 23526464). 23526464
RET M918T thyroid medullary carcinoma sensitive XMD15-44 Preclinical Actionable In a preclinical study, XMD15-44 inhibited RET phosphorylation and downstream signaling and reduced proliferation of medullary thyroid carcinoma cells harboring RET M918T in culture (PMID: 26046350). 26046350
RET M918T thyroid medullary carcinoma sensitive LOXO-292 Preclinical - Cell culture Actionable In a preclinical study, thyroid medullary carcinoma cells harboring RET M918T were sensitive to treatment with LOXO-292 in culture, demonstrating decreased cell proliferation (PMID: 29912274). 29912274
RET M918T thyroid medullary carcinoma sensitive HG-6-63-01 Preclinical Actionable In a preclinical study, HG-6-63-01 inhibited RET phosphorylation and downstream signaling and reduced proliferation of medullary thyroid carcinoma cells harboring RET M918T in culture (PMID: 26046350). 26046350
RET M918T lung small cell carcinoma sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of small cell lung carcinoma lines expressing RET M918T (PMID: 25122427). 25122427
RET M918T thyroid medullary carcinoma sensitive ALW-II-41-27 Preclinical - Cell culture Actionable In a preclinical study, ALW-II-41-27 inhibited RET phosphorylation and downstream signaling and reduced proliferation of medullary thryoid carcinoma cells harboring RET M918T in culture (PMID: 26046350). 26046350
RET M918T thyroid medullary carcinoma sensitive Cabozantinib Phase III Actionable In a Phase III trial, Cometriq (cabozantinib) treatment resulted in improved progression free survival (61 vs 17 weeks) compared to placebo in thyroid medullary carcinoma patients harboring RET M918T (PMID: 27525386). 27525386
RET M918T thyroid medullary carcinoma sensitive Cabozantinib Phase III Actionable In a Phase III trial, Cometriq (cabozantinib) increased overall survival to 25.4 months in medullary thyroid carcinoma patients with RET M918T (J Clin Oncol 33, 2015, suppl; abstr 6012). detail...
RET M918T Advanced Solid Tumor sensitive ALW-II-41-27 Preclinical - Cell culture Actionable In a preclinical study, ALW-II-41-27 inhibited RET phosphorylation and downstream signaling, reduced proliferation of transformed cells expressing RET M918T in culture (PMID: 26046350). 26046350
RET M918T thyroid medullary carcinoma predicted - sensitive Sorafenib Phase II Actionable In a Phase II trial, Nexavar (sorafenib) treatment resulted in partial response in 10% (1/10) and stable disease in 90% (9/10) of patients with medullary thyroid carcinoma harboring RET M918T (PMID: 20368568). 20368568
RET M918T Advanced Solid Tumor predicted - sensitive Pz-1 Preclinical Actionable In a preclinical study, Pz-1 inhibited Ret phosphorylation in transformed cells expressing RET M918T (PMID: 26126987). 26126987
RET M918T thyroid medullary carcinoma sensitive AZD1480 Preclinical - Cell culture Actionable In a preclinical study, AZD1480 reduced phosphorylation of RET and downstream effectors, and inhibited growth and increased apoptosis of a medullary thyroid cancer cell line harboring RET M918T in culture (PMID: 23056499). 23056499
RET M918T lung small cell carcinoma sensitive Vandetanib Preclinical Actionable In a preclinical study, Caprelsa (vandetanib) inhibited growth of small cell lung carcinoma lines expressing RET M918T (PMID: 25122427). 25122427
RET M918T thyroid medullary carcinoma sensitive Everolimus Phase II Actionable In a Phase II clinical trial, Afinitor (everolimus) treatment resulted in stable disease in 71% (5/7) of medullary thyroid cancer patients, and 4 of the 7 patients carried a RET M918T mutation (PMID: 26294908). 26294908
RET M918T colorectal cancer sensitive Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and decreased growth of colorectal cancer cells harboring a RET M918T mutation in culture (PMID: 17664273). 17664273
RET M918T Advanced Solid Tumor sensitive Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and decreased proliferation of cells expressing RET M918T in culture (PMID: 17664273). 17664273
RET M918T Advanced Solid Tumor sensitive HG-6-63-01 Preclinical Actionable In a preclinical study, HG-6-63-01 inhibited RET phosphorylation and downstream signaling and reduced proliferation of transformed cells expressing RET M918T in culture (PMID: 26046350). 26046350
RET C634F thyroid medullary carcinoma predicted - sensitive Sorafenib Phase II Actionable In a Phase II trial, Nexavar (sorafenib) treatment resulted in stable disease in one patient with medullary thyroid carcinoma harboring RET C634F (PMID: 20368568). 20368568
RET V804X thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET V804X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with increased risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET A883F Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET A883F in culture (PMID: 23526464). 23526464
RET A883F Advanced Solid Tumor sensitive Vandetanib Preclinical Actionable In a preclinical study, Caprelsa (vandetanib) inhibited Ret autophosphorylation in transformed cells expressing RET A883F in culture (PMID: 15184865). 15184865
RET Y791X thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET Y791X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with increased risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET fusion non-small cell lung carcinoma sensitive LOXO-292 Phase I Actionable In a Phase I trial, LOXO-292 treatment resulted in an objective response rate of 65% (17/26) in RET fusion-positive non-small cell lung cancer patients (J Clin Oncol 36, 2018 (suppl; abstr 102); NCT03157128). detail...
RET fusion papillary thyroid carcinoma sensitive LOXO-292 Phase I Actionable In a Phase I trial, LOXO-292 treatment resulted in an objective response rate of 83% (5/6) in RET fusion-positive papillary thyroid cancer patients (J Clin Oncol 36, 2018 (suppl; abstr 102); NCT03157128). detail...
RET fusion non-small cell lung carcinoma sensitive Vandetanib Phase II Actionable In a Phase II trial, Caprelsa (vandetanib) treatment resulted in a disease control rate of 88% (15/17), median progression-free survival (PFS) of 4.7 months, and partial response in 53% (9/17) of non-small cell lung adenocarcinoma patients harboring RET fusions (J Clin Oncol 34, 2016 (suppl; abstr 9012)). detail...
RET fusion non-small cell lung carcinoma sensitive Vandetanib Phase II Actionable In a Phase II trial, Caprelsa (vandetanib) treatment resulted in partial remission in 17% (3/18) and stable disease in 44% (8/18) of non-small cell lung adenocarcinoma patients harboring RET fusions (J Clin Oncol 34, 2016 (suppl; abstr 9013)). detail...
RET act mut non-small cell lung carcinoma sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited RET phosphorylation and reduced viability of non-small cell lung cancer cells with RET activating mutations (Cancer Res April 15, 2013 73; 2084). detail...
RET C618X thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET C618X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET E884K Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET E884K in culture (PMID: 23526464). 23526464
RET M918X thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET M918X mutations result in multiple endocrine neoplasia, type 2B (MEN 2B), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET C630X thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET C630X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET wild-type lung small cell carcinoma sensitive Vandetanib Preclinical Actionable In a preclinical study, Caprelsa (vandetanib) inhibited growth of small cell lung carcinoma lines expressing wild-type RET (PMID: 25122427). 25122427
RET wild-type lung small cell carcinoma sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of small cell lung carcinoma lines expressing wild-type RET (PMID: 25122427). 25122427
RET Y791F Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET Y971F in culture (PMID: 23526464). 23526464
RET Y791F Advanced Solid Tumor sensitive Vandetanib Preclinical Actionable In a preclinical study, Caprelsa (vandetanib) inhibited Ret autophosphorylation in transformed cells expressing RET Y791F in culture (PMID: 15184865). 15184865
RET C634X thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET C634X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET E768X thyroid medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET E768X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with increased risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET mutant thyroid medullary carcinoma sensitive LOXO-292 Phase I Actionable In a Phase I trial, LOXO-292 treatment resulted in partial response in 14% (2/14) and tumor reduction in 79% (11/14) of RET mutant thyroid medullary cancer patients (J Clin Oncol 36, 2018 (suppl; abstr 102); NCT03157128). detail...
RET mutant thyroid medullary carcinoma sensitive Cabozantinib Phase III Actionable In a Phase III trial, Cometriq (cabozantinib) treatment resulted in improved progression free survival (60 vs 20 weeks) compared to placebo in thyroid medullary carcinoma patients harboring RET mutations (PMID: 27525386). 27525386
RET mutant cancer sensitive Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) inhibited wild-type RET and RET mutations to prevent cell proliferation in cell culture (PMID: 17664273). 17664273
RET mutant colorectal cancer sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) demonstrated efficacy in RET mutant positive colorectal cancer cell lines (PMID: 23811235). 23811235
RET mutant Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Iclusig (ponatinib) inhibited proliferation of cancer cell lines harboring RET mutations in cultured and in cell line xenograft models (PMID: 23526464). 23526464
RET mutant thyroid medullary carcinoma sensitive Everolimus Phase II Actionable In a Phase II clinical trial, Afinitor (everolimus) treatment resulted in stable disease in 71% (5/7) of medullary thyroid cancer patients, including patients harboring RET mutations, with median progression-free survival of 33 weeks (PMID: 26294908). 26294908
KDR pos RET C634W thyroid medullary carcinoma predicted - sensitive Motesanib Preclinical - Cell line xenograft Actionable In a preclinical study, Motesanib (AMG 706) inhibited KDR (VEGFR2) phosphorylation, but had minimal activity against RET in a medullary thyroid carcinoma (MTC) cell line harboring RET C634W in culture, however, inhibited both RET and KDR (VEGFR2) phosphorylation and decreased tumor angiogenesis and growth in MTC cell line xenograft models with RET C634W (PMID: 21422803). 21422803
RET C634W thyroid carcinoma sensitive Ponatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Iclusig (ponatinib) inhibited RET signaling and decreased growth of thyroid carcinoma cells harboring a RET C634W mutation in culture and in cell line xenograft models (PMID: 23526464). 23526464
RET C634W thyroid medullary carcinoma sensitive LOXO-292 Preclinical - Cell line xenograft Actionable In a preclinical study, thyroid medullary carcinoma cells harboring RET C634W were sensitive to treatment with LOXO-292, demonstrating decreased cell proliferation in culture and inhibition of tumor growth in cell line xenograft models (PMID: 29912274). 29912274
RET C634W thyroid cancer sensitive Regorafenib Preclinical - Cell culture Actionable In a preclinical study, Stivarga (regorafenib) inhibited proliferation of thyroid cancer cells harboring RET C634W in culture (PMID: 21170960). 21170960
RET C634W thyroid cancer sensitive Lenvatinib Preclinical Actionable In a preclinical study, Lenvima (lenvatinib) inhibited RET phosphorylation and signaling in thyroid cancer cells expressing RET C634W (PMID: 25295214). 25295214
RET C634W thyroid medullary carcinoma sensitive Sorafenib Preclinical - Cell line xenograft Actionable In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and inhibited tumor growth in cell line xenograft models of medullary thyroid carcinoma harboring RET C634W (PMID: 16507829). 16507829
RET C634W thyroid carcinoma sensitive Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and decreased growth of thyroid carcinoma cells harboring a RET C634W mutation in culture (PMID: 17664273). 17664273
RET C634W thyroid medullary carcinoma sensitive CEP-32496 Preclinical - Cell culture Actionable In a preclinical study, RXDX-105 (CEP-32496) reduced phosphorylation of RET and downstream signaling and inhibited proliferation of a medullary thyroid cancer cell line harboring RET C634W in culture (PMID: 28011461). 28011461
RET C634W thyroid medullary carcinoma sensitive ALW-II-41-27 Preclinical - Cell culture Actionable In a preclinical study, ALW-II-41-27 inhibited RET phosphorylation and downstream signaling and reduced proliferation of medullary thyroid carcinoma cells harboring RET C634W in culture (PMID: 26046350). 26046350
RET C634W thyroid medullary carcinoma sensitive HG-6-63-01 Preclinical Actionable In a preclinical study, HG-6-63-01 inhibited RET phosphorylation and downstream signaling and reduced proliferation of medullary thyroid carcinoma cells harboring RET C634W in culture (PMID: 26046350). 26046350
RET C634W thyroid carcinoma sensitive Cabozantinib Preclinical - Cell line xenograft Actionable In a preclinical study, Cometriq (cabozantinib) inhibited phosphorylation of RET C634W and decreased tumor growth in xenograft models of a human thyroid carcinoma cell line harboring RET C634W mutation (PMID: 23705946). 23705946
RET C634W thyroid medullary carcinoma sensitive XMD15-44 Preclinical Actionable In a preclinical study, XMD15-44 inhibited RET phosphorylation and downstream signaling and reduced proliferation of medullary thyroid carcinoma cells harboring RET C634W in culture (PMID: 26046350). 26046350
RET C634W thyroid medullary carcinoma sensitive BLU-667 Preclinical - Cell line xenograft Actionable In a preclinical study, BLU-667 inhibited Ret signaling and proliferation of a medullary thyroid cancer cell line harboring RET C634W in culture, and inhibited tumor growth in xenograft models (PMID: 29657135). detail... 29657135
RET C634W thyroid cancer sensitive AZD1480 Preclinical - Cell culture Actionable In a preclinical study, AZD1480 reduced phosphorylation of RET and downstream effectors, and inhibited growth and increased apoptosis of a thyroid cancer cell line harboring RET C634W in culture (PMID: 23056499). 23056499
ROS1 fusion ERBB2 amp FGFR3 amp RET amp non-small cell lung carcinoma predicted - resistant Crizotinib Clinical Study Actionable In a clinical study, a non-small cell lung carcinoma patient harboring a ROS1 fusion treated with Xalkori (crizotinib) responded, but eventually progressed, and was subsequently found to harbor presumed resistance alterations, including amplification of ERBB2 (HER2), FGFR3, and RET (PMID: 29636358). 29636358
RET D898V Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET D898V in culture (PMID: 23526464). 23526464