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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, PMID: 32094155). RET germline mutations result in MEN2 syndromes and familial medullary thyroid carcinoma (PMID: 20930041, PMID: 24561444) and somatic RET activating mutations, fusions, and Ret amplification and/or 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, Familial medullary thyroid carcinoma (PMID: 27854360)
Yes, Multiple endocrine neoplasia, type 2a (PMID: 27854360)
Yes, Multiple endocrine neoplasia, type 2b (PMID: 27854360)

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Variant Impact Protein Effect Variant Description Associated with drug Resistance
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.
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, Jan 2020).
A756D missense unknown RET A756D lies within the protein kinase domain of the Ret protein (UniProt.org). A756D has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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 biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Nov 2019).
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, Apr 2020). Y
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).
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.
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.
A919V missense unknown RET A919V lies within the protein kinase domain of the Ret protein (UniProt.org). A919V is predicted to result in decreased Ret protein stability in computational models (PMID: 16928683, PMID: 19186126), but has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2019).
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.
amp none no effect RET amp indicates an increased number of copies of the RET gene. However, the mechanism causing the increase is unspecified.
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).
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).
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, Jan 2020).
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: 30763276, PMID: 24699901), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
C609R missense gain of function - predicted RET C609R lies within the extracellular domain of the Ret protein (UniProt.org). C609R reduces cell surface Ret expression, but also results in increased Ret and Shc phosphorylation, activation of transcription in reporter assays, and is transforming in cell culture (PMID: 9879991), therefore, is predicted to lead to a gain of Ret protein function.
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).
C609W missense unknown RET C609W lies within the extracellular domain of the Ret protein (UniProt.org). C609W has dual effects on Ret protein function, as 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).
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.
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).
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, Jan 2020).
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, PMID: 30763276), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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: 30446652, PMID: 25163725), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Mar 2020). Y
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, Jan 2020).
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.
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.
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).
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.
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).
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.
C618W missense unknown RET C618W lies within the extracellular domain of the Ret protein (UniProt.org). C618W has been identified in sequencing studies (PMID: 17384210, PMID: 14718397), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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.
C618Y missense gain of function RET C618Y lies within the extracellular domain of the Ret protein (UniProt.org). C618Y results in increased phosphorylation of Akt and Erk1/2, promotes colony formation (PMID: 31364476), and is transforming in cell culture (PMID: 9230192).
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: 29515777, PMID: 25694125), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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: 30763276, PMID: 22584707), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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).
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.
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, Jan 2020).
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.
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).
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).
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, Nov 2019).
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).
C630S missense unknown RET C630S lies within the cysteine-rich region of the Ret protein (PMID: 9879991). C630S has been identified in the scientific literature (PMID: 28676824, PMID: 15523405), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Nov 2019).
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.
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.
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.
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.
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).
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).
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).
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).
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.
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).
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).
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, Nov 2019).
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, Nov 2019).
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, Nov 2019).
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).
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 one glutamic acid (E) at the same site (UniProt.org). D631_L633delinsE has been identified in the scientific literature (PMID: 27082517), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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 one 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, Jan 2020).
D707N missense loss of function RET D707N lies within a caspase-3 cleavage site of the Ret protein (PMID: 10921886). D707N confers a loss of function to the Ret protein as demonstrated by impaired caspase-induced cleavage and apoptosis (PMID: 10921886, PMID: 21357690), decreased GDNF-induced Erk phosphorylation, and reduced interaction with P120 and N-cadherin (PMID: 21357690).
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 downstream 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).
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 biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
E1006D missense unknown RET E1006D lies within the protein kinase domain of the Ret protein (UniProt.org). E1006D has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
E136K missense unknown RET E136K lies within the extracellular domain 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, Jan 2020).
E505_G506del deletion gain of function RET E505_G506del results in the deletion of 2 amino acids in the extracellular 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).
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).
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 biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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, Jan 2020).
E632K missense unknown RET E632K lies within the extracellular domain of the Ret protein (UniProt.org). E632K has been identified in sequencing studies (PMID: 27756406), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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.
E632_T636delinsSS indel unknown RET E632_T636delinsSS results in the deletion of five amino acids of the Ret protein from amino acids 632 to 636, combined with the insertion of two serine (S) at the same site (UniProt.org). E632_T636delinsSS has been identified in sequencing studies (PMID: 9160884), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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, Apr 2020). Y
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 downstream 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).
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).
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).
E768N missense unknown RET E768N lies within the protein kinase domain of the Ret protein (UniProt.org). E768N has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2019).
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.
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.
E884K missense unknown RET E884K lies within the protein kinase domain and substrate recognition region of the Ret protein (PMID: 10622534, UniProt.org). E884K has been identified in the scientific literature (PMID: 10622534, PMID: 19029224, PMID: 28351340), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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).
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, Jan 2020).
F329L missense unknown RET F329L lies within the extracellular domain of the Ret protein (UniProt.org). F329L has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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 biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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).
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, Apr 2020). Y
fusion fusion unknown RET fusion indicates a fusion of the RET gene, but the fusion partner is unknown.
G10C missense unknown RET G10C lies within the signal peptide region of the Ret protein (UniProt.org). G10C has been identified in the scientific literature (PMID: 32094155), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, May 2020).
G10R missense unknown RET G10R lies within the signal peptide region of the Ret protein (UniProt.org). G10R has been identified in the scientific literature (PMID: 32094155), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, May 2020).
G10S missense unknown RET G10S lies within the signal peptide region of the Ret protein (UniProt.org). G10S has been identified in the scientific literature (PMID: 32094155), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, May 2020).
G446R missense unknown RET G446R lies within the extracellular domain of the Ret protein (UniProt.org). G446R 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, Jan 2020).
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).
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, Jan 2020).
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).
G736R missense unknown RET G736R lies within the protein kinase domain of the Ret protein (UniProt.org). G736R has been identified in the scientific literature (PMID: 26076779), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
G810A missense unknown RET G810A lies within the protein kinase domain of the Ret protein (UniProt.org). G810A has been demonstrated to confer drug resistance (PMID: 31118272) and in the context of KIF5B-RET in culture (PMID: 27496134), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Mar 2020). Y
G810C missense unknown RET G810C lies within the protein kinase domain of the Ret protein (UniProt.org). G810C is associated with RET inhibitor resistance in the context of RET fusions (PMID: 31988000), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020). Y
G810R missense unknown RET G810R lies within the protein kinase domain of the Ret protein (UniProt.org). G810R is associated with RET inhibitor resistance in the context of RET fusions (PMID: 31988000), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020). Y
G810S missense unknown RET G810S lies within the protein kinase domain of the Ret protein (UniProt.org). G810S has been demonstrated to confer resistance to tyrosine kinase inhibitors in the context of RET fusions (PMID: 29908090, PMID: 31988000), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2020). Y
I788N missense unknown RET I788N lies within the protein kinase domain of the Ret protein (UniProt.org). I788N has been associated with drug 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, Apr 2020). 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).
inact mut unknown loss of function RET inact mut indicates that this variant results in a loss of function of the Ret protein. However, the specific amino acid change has not been identified.
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).
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 downstream 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).
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.
L517V missense unknown RET L517V lies within the extracellular domain of the Ret protein (UniProt.org). L517V has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
L56M missense no effect RET L56M lies within the extracellular domain of the Ret protein (UniProt.org). L56M does not effect Ret extracellular domain secretion (PMID: 20473317), and results in similar phosphorylation of Ret, Stat3, and Erk to wild-type Ret in culture (PMID: 31649719).
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, Jan 2020).
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).
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, Apr 2020). Y
L730V missense unknown RET L730V lies within the protein kinase domain of the Ret protein (UniProt.org). L730V has been demonstrated to confer resistance to tyrosine kinase inhibitors 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, Apr 2020). Y
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 it results in ligand-independent activation of Ret (PMID: 15184865), however, also results in similar cell proliferation and transformation activity to wild-type Ret in cell culture (PMID: 21810974), and therefore, its effect on Ret protein function is unknown.
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.
L881V missense unknown RET L881V lies within the protein kinase domain of the Ret protein (UniProt.org). L881V has been demonstrated to confer resistance to some RET inhibitors in the context of KIF5B-RET in cultured cells (PMID: 31118272), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2020). Y
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, Jan 2020).
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, Jan 2020).
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: 27149458, PMID: 24429398), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Mar 2020).
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, Apr 2020).
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.
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
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.
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.
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).
mutant unknown unknown RET mutant indicates an unspecified mutation in the RET gene.
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.
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.
P1070S missense unknown RET P1070S lies within the cytoplasmic domain of the Ret protein (UniProt.org). P1070S has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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, Jan 2020).
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.
positive unknown unknown RET positive indicates the presence of the RET gene, mRNA, and/or protein.
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, Jan 2020).
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, Nov 2019).
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.
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.
R57W missense unknown RET R57W lies within the extracellular domain of the Ret protein (UniProt.org). R57W has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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, Jan 2020).
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, Jan 2020).
R721W missense unknown RET R721W lies within the cytoplasmic domain of the Ret protein (UniProt.org). R721W has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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: 28196074, PMID: 25425582), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
R77H missense unknown RET R77H lies within the extracellular domain of the Ret protein (UniProt.org). R77H has been identified in sequencing studies (PMID: 27626691, PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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: 25530832, PMID: 29681454), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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).
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).
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).
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: 27998968, PMID: 22622578, PMID: 22722839), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
R886W missense gain of function RET R886W lies within the protein kinase domain of the Ret protein (UniProt.org). R886W confers a gain of function to the Ret protein as demonstrated by increased Erk1/2, Stat1/3, and Tcf activation and transformation of cultured cells (PMID: 21551259).
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).
R912L missense unknown RET R912L lies within the protein kinase domain of the Ret protein (UniProt.org). R912L has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
R912P missense gain of function - predicted RET R912P lies within the protein kinase domain of the Ret protein (UniProt.org). R912P results in activation of ligand-independent signaling as demonstrated by increased phospho-Mapk compared to wild-type Ret in culture (PMID: 29625052), and therefore, is predicted to lead to gain of Ret protein function.
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).
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, Jan 2020).
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).
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.
rearrange unknown unknown RET rearrangement indicates an unspecified rearrangement of the RET gene.
S409Y missense gain of function RET S409Y lies within the extracellular domain of the Ret protein (UniProt.org). S409Y results in increased phosphorylation of Akt and Erk, and promotes colony formation in cell culture (PMID: 31364476).
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).
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).
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).
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).
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, Jan 2020).
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.
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, PMID: 17047083), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
S904F missense unknown RET S904F lies within the protein kinase domain of the Ret protein (UniProt.org). S904F has been associated with drug resistance in the context of CCDC6-RET (PMID: 29434222), and results in increased foci formation and autophosphorylation, but demonstrates cell proliferation similar to wild-type in culture (PMID: 21810974, PMID: 29434222), and therefore, its effect on Ret protein function is unknown. Y
S936F missense unknown RET S936F lies within the protein kinase domain of the Ret protein (UniProt.org). S936F has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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, Jan 2020).
T1038A missense unknown RET T1038A lies within the cytoplasmic domain of the Ret protein (UniProt.org). T1038A has 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, Apr 2020).
T278N missense unknown RET T278N lies within the extracellular domain of the Ret protein (UniProt.org). T278N has been identified in sequencing studies (PMID: 30214228, PMID: 24845513, PMID: 20668451), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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, Jan 2020).
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), and therefore, its effect on Ret protein function is unknown.
T742M missense unknown RET T742M lies within the protein kinase domain of the Ret protein (UniProt.org). T742M has not been characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
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, Jan 2020).
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, Jan 2020).
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).
V637M missense unknown RET V637M lies within the transmembrane 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, Jan 2020).
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, Jan 2020).
V648I missense unknown RET V648I lies within the transmembrane domain of the Ret protein (UniProt.org). V648I results in increased cell proliferation, but is not transforming in cell culture (PMID: 21810974), and therefore, its effect on Ret protein function is unknown.
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, Apr 2020). Y
V778I missense unknown RET V778I lies within the protein kinase domain of the Ret protein (UniProt.org). V778I has been identified in the scientific literature (PMID: 11732489, PMID: 31300450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2020).
V804E missense unknown RET V804E lies within the protein kinase domain of the Ret protein (UniProt.org). V804E has been demonstrated to confer drug resistance 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, Apr 2020). Y
V804G missense unknown RET V804G lies within the protein kinase domain of the Ret protein (UniProt.org). V804G in combination with C634R results in moderately decreased Ret kinase activity and transformation activity compared to C634R alone in cell culture (PMID: 15184865), but has not been characterized individually and therefore, its effect on Ret protein function is unknown (PubMed, Nov 2019).
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
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
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.
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, Jan 2020). Y
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, Jan 2020).
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.
wild-type none no effect Wild-type RET indicates that no mutation has been detected within the RET gene.
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).
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).
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.
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
Y806E missense unknown RET Y806E lies within the protein kinase domain of the Ret protein (UniProt.org). Y806E has been demonstrated to confer secondary drug resistance 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, Nov 2019). Y
Y806F missense unknown RET Y806F lies within the protein kinase domain of the Ret protein (UniProt.org). Y806F results in reduced autophosphorylation and transforming activity in the context of a constitutively active form of RET (PMID: 14711813), but has not been individually characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2020).
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, Apr 2020). Y