Gene Detail

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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 results in GDNF-dependent Mapk activation to a similar level as 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, Feb 2024).
A510V	missense	gain of function	RET A510V lies within the extracellular domain of the Ret protein (UniProt.org). A510V confers a gain of function to Ret as demonstrated by increased Ret and Erk phosphorylation and transformation in cultured cells (PMID: 20103606).
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, Feb 2024).
A756V	missense	loss of function - predicted	RET A756V lies within the protein kinase domain of the Ret protein (UniProt.org). A756V results in reduced phosphorylation of Ret and Erk in cell culture (PMID: 26395553), and therefore, is predicted to lead to a loss of Ret protein function.
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, Aug 2024).	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 (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 biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2024).
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).
C531R	missense	gain of function	RET C531R lies within the extracellular domain of the Ret protein (UniProt.org). C531R confers a gain of function to Ret as demonstrated by increased Ret and Erk phosphorylation and transformation in cultured cells (PMID: 20103606).
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, Feb 2024).
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, Feb 2024).
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 results in ligand-independent Ret autophosphorylation in culture (PMID: 16343103), and therefore, is predicted to lead to a gain of Ret protein function.
C609W	missense	unknown	RET C609W lies within the extracellular domain of the Ret protein (UniProt.org). The functional effect of C609W is conflicting 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), and therefore, its effect on Ret protein function is unknown.
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, PMID: 33827484), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
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, Feb 2024).
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, Feb 2024).
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, Feb 2024).
C611W	missense	gain of function - predicted	RET C611W lies within the extracellular domain of the Ret protein (UniProt.org). C611W is transforming in cell culture (PMID: 9230192), and therefore, is predicted to lead to a gain of Ret protein function.
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).
C618F	missense	gain of function - predicted	RET C618F lies within the extracellular domain of the Ret protein (UniProt.org). C618F results in elevated basal and ligand-induced phosphorylation levels and decreased cell surface expression in culture (PMID: 30884088), and therefore, is predicted to lead to a gain of Ret protein function.
C618G	missense	gain of function - predicted	RET C618G lies within the extracellular domain of the Ret protein (UniProt.org). C618G is transforming in cell culture (PMID: 9230192), and therefore, is predicted to lead to a gain of Ret protein function.
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 is transforming in cell culture (PMID: 9230192), and therefore, is predicted to lead to a gain of Ret protein function.
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, Feb 2024).
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, Feb 2024).
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, Feb 2024).
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, transformation in cell culture (PMID: 9879991, PMID: 9230192), increased Erk phosphorylation and IL3-independent growth in culture (PMID: 36166639).
C620S	missense	gain of function - predicted	RET C620S lies within the extracellular domain of the Ret protein (UniProt.org). C620S is transforming in cell culture (PMID: 9230192), and therefore, is predicted to lead to a gain of Ret protein function.
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, Feb 2024).
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).
C630del	deletion	gain of function	RET C630del results in the deletion of an amino acid in the cysteine-rich region of the Ret protein at amino acid 630 (UniProt.org). C630del results in increased Ret phosphorylation, downstream signaling, viability, and colony formation in cultured cells (PMID: 35689816).
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 the scientific literature (PMID: 32031055, PMID: 35470851), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
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, PMID: 35574005), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
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	RET C630Y lies within the extracellular domain of the Ret protein (UniProt.org). C630Y results in increased phosphorylation of Ret, Akt, and Pi3k, increased colony formation and migration (PMID: 34905813), and is transforming in culture (PMID: 10049754).
C634F	missense	gain of function - predicted	RET C634F lies within the cysteine-rich region of the Ret protein (PMID: 9879991). C634F is transforming in cell culture (PMID: 9230192), and therefore, is predicted to lead to a gain of Ret protein function.
C634G	missense	gain of function - predicted	RET C634G lies within the cysteine-rich region of the Ret protein (PMID: 9879991). C634G is transforming in cell culture (PMID: 9230192), and therefore, is predicted to lead to a gain of Ret protein function.
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_A640dup	duplication	unknown	RET C634_A640dup indicates the insertion of 7 duplicate amino acids, cysteine (C)-634 through alanine (A)-640, in the helical domain of the Ret protein (UniProt.org). C634_A640dup has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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).
D378_G385delinsE	indel	unknown	RET D378_G385delinsE results in a deletion of eight amino acids within the extracellular domain of the Ret protein from amino acid 378 to 385, combined with the insertion of a glutamic acid (E) at the same location (UniProt.org). D378_G385delinsE has been identified in the scientific literature (PMID: 32923911), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
D489N	missense	no effect - predicted	RET D489N lies within the extracellular domain of the Ret protein (UniProt.org). D489N results in phosphorylation of Ret and Erk similar to wild-type protein in cell culture (PMID: 26395553), and therefore, is predicted to have no effect on Ret protein function.
D567N	missense	gain of function	RET D567N lies within the extracellular domain of the Ret protein (UniProt.org). D567N results in increased phosphorylation of Ret and Erk, IL3-independent growth in culture, and tumor formation in a mouse model (PMID: 36166639).
D567Y	missense	gain of function	RET D567Y lies within the extracellular domain of the Ret protein (UniProt.org). D567Y results in increased phosphorylation of Ret and Erk, IL3-independent growth in culture, and tumor formation in a mouse model (PMID: 36166639).
D571N	missense	gain of function	RET D571N lies within the extracellular domain of the Ret protein (UniProt.org). D571N confers a gain of function to Ret as demonstrated by increased Erk phosphorylation and IL3-independent growth in culture (PMID: 36166639).
D584N	missense	gain of function	RET D584N lies within the extracellular domain of the Ret protein (UniProt.org). D584N confers a gain of function to Ret as demonstrated by increased Erk phosphorylation and IL3-independent growth in culture (PMID: 36166639).
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.
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.
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.
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 (PMID: 10049754), increased Erk phosphorylation (PMID: 36166639), and transformation of cultured cells (PMID: 10049754, PMID: 36166639).
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, Jun 2024).
D631_L633delinsS	indel	unknown	RET D631_L633delinsS 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 serine (S) at the same site (UniProt.org). D631_L633delinsS has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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, Jun 2024).
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, Feb 2024).
D898_E901del	deletion	gain of function	RET D898_E901del results in the deletion of four amino acids in the protein kinase domain of the Ret protein from amino acids 898 to 901 (UniProt.org). D898_E901del confers a gain of function to Ret as demonstrated by increased Erk phosphorylation (PMID: 32284345), increased Ret phosphorlyation, (PMID: 37535881), cytokine-independent growth in culture (PMID: 32284345, PMID: 37535881), and tumor formation in a mouse model (PMID: 37535881).
D925H	missense	unknown	RET D925H lies within the protein kinase domain of the Ret protein (UniProt.org). D925H has been identified in sequencing studies (PMID: 8825918, PMID: 30446652), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
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, Feb 2024).
E136K	missense	unknown	RET E136K lies within the extracellular domain of the Ret protein (UniProt.org). E136K has been identified in sequencing studies (PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
E232K	missense	unknown	RET E232K lies within the cadherin domain of the Ret protein (UniProt.org). E232K has been identified in sequencing studies (PMID: 30446652), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
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).
E511K	missense	gain of function	RET E511K lies within the extracellular domain of the Ret protein (UniProt.org). E511K confers a gain of function to Ret as demonstrated by increased Ret and Erk phosphorylation and transformation in cultured cells (PMID: 20103606).
E574D	missense	gain of function	RET E574D lies within the extracellular domain of the Ret protein (UniProt.org). E574D confers a gain of function to Ret as demonstrated by increased Erk phosphorylation and IL3-independent growth in culture (PMID: 36166639).
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).
E61del	deletion	unknown	RET E61del results in the deletion of an amino acid in the extracellular domain of the Ret protein at amino acid 61 (UniProt.org). E61del has been identified in sequencing studies (PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
E623G	missense	unknown	RET E623G lies within the extracellular domain of the Ret protein (UniProt.org). E623G has been identified in sequencing studies (PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
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, Feb 2024).
E623_L633del	deletion	unknown	RET E623_L633del results in the deletion of 11 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, Apr 2024).
E632K	missense	unknown	RET E632K lies within the extracellular domain of the Ret protein (UniProt.org). E632K has been identified in sequencing studies (PMID: 30115035, PMID: 27756406, PMID: 33257508), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2024).
E632_A639delinsHR	indel	unknown	RET E632_A639delinsHR results in a deletion of eight amino acids in the extracellular domain of the Ret protein from amino acids 632 to 639, combined with the insertion of a histidine (H) and an arginine (R) at the same site (UniProt.org). E632_A639delinsHR has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
E632_C634del	deletion	unknown	RET E632_C634del results in the deletion of three amino acids in the extracellular domain of the Ret protein from amino acids 632 to 634 (UniProt.org). E632_C634del has been identified in the scientific literature (PMID: 35616103, PMID: 31605946), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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 (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 serines (S) at the same site (UniProt.org). E632_T636delinsSS results in increased transformation compared to wild-type in cell culture (PMID: 39095584), and therefore, is predicted to lead to gain of Ret protein function.
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, Aug 2024).	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 concurrent 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 been identified in the scientific literature (PMID: 31145454), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
E768Q	missense	unknown	RET E768Q lies within the protein kinase domain of the Ret protein (UniProt.org). E768Q has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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	unknown	RET E805K lies within the protein kinase domain of the Ret protein (UniProt.org). E805K leads to enhanced transformation ability in combination with V804M, however, demonstrates weak transformation activity upon stimulation in the long isoform, and does not result in transformation activity in response to ligand in the short isoform (PMID: 17047083), and therefore, its effect on Ret protein function is unknown.
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 biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
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 concurrent 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, Apr 2024).
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, Feb 2024).
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, Apr 2024).
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 concurrent 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, Aug 2024).	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, Aug 2024).
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, Aug 2024).
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, Aug 2024).
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, Feb 2024).
G533C	missense	gain of function	RET G533C lies within the extracellular domain of the Ret protein (UniProt.org). G553C results in increased Erk phosphorylation (PMID: 36166639) and Ret autophosphorylation, enhanced cell proliferation, micronuclei formation, and colony formation, decreased apoptosis and expression of thyroid-specific genes in culture (PMID: 21834681), transformation in culture (PMID: 36166639), and increased liver metastasis in mouse models (PMID: 21834681).
G533S	missense	no effect - predicted	RET G533S lies within the extracellular domain of the Ret protein (UniProt.org). G533S results in phosphorylation of Ret and Erk similar to wild-type protein in cell culture (PMID: 26395553), and therefore, is predicted to have no effect on Ret protein function.
G592_G607del	deletion	unknown	RET G592_G607del results in the deletion of 16 amino acids in the extracellular domain of the Ret protein from amino acids 592 to 607 (UniProt.org). G592_G607del has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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, Feb 2024).
G607C	missense	gain of function	RET G607C lies within the extracellular domain of the Ret protein (UniProt.org). G607C confers a gain of function to Ret as demonstrated by increased Erk phosphorylation and IL3-independent growth in culture (PMID: 36166639).
G691S	missense	unknown	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), but in another study results in focus formation and proliferation similar to wild-type RET in cultured cells (PMID: 21810974), and therefore, its effect on Ret protein function is unknown.
G736A	missense	unknown	RET G736A lies within the protein kinase domain of the Ret protein (UniProt.org). G736A has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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, Feb 2024).
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 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, Jun 2024).	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, PMID: 33161056), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2024).	Y
G810D	missense	unknown	RET G810D lies within the protein kinase domain of the Ret protein (UniProt.org). G810D has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
G810N	missense	unknown	RET G810N lies within the protein kinase domain of the Ret protein (UniProt.org). G810N has been associated with acquired resistance to RET inhibitors (PMID: 38127829), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).	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, PMID: 33161056, PMID: 34373541), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2024).	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, PMID: 36996322), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).	Y
I590_G607del	deletion	unknown	RET I590_G607del results in the deletion of 18 amino acids in the extracellular domain of the Ret protein from amino acids 590 to 607 (UniProt.org). I590_G607del has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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, PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).	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.
K662M	missense	unknown	RET K662M lies within the cytoplasmic domain of the Ret protein (UniProt.org). K662M has been identified in sequencing studies (PMID: 34741450, PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
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).
K666N	missense	gain of function	RET K666N lies within the cytoplasmic domain of the Ret protein (UniProt.org). K666N results in increased Ret autophosphorylation and Erk phosphorylation and is transforming in culture (PMID: 20103606).
K758M	missense	loss of function	RET K758M lies within the protein kinase domain of the Ret protein (UniProt.org). K758M 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).
K780T	missense	unknown	RET K780T lies within the protein kinase domain of the Ret protein (UniProt.org). K780T has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
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 concurrent activating RET mutation (C634R) in culture (PMID: 9502784), and therefore, is predicted to lead to a loss of Ret protein function.
L1016S	missense	unknown	RET L1016S lies within the protein kinase domain of the Ret protein (UniProt.org). L1016S has been identified in the scientific literature (PMID: 36053791), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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, Feb 2024).
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, Feb 2024).
L629_D631delinsH	indel	unknown	RET L629_D631delinsH results in a deletion of three amino acids in the extracellular domain of the Ret protein from amino acids 629 to 631, combined with the insertion of one histidine (H) at the same site (UniProt.org). L629_D631delinsH has been identified in the scientific literature (PMID: 35616103, PMID: 31605946), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
L629_L633del	deletion	unknown	RET L629_L633del results in the deletion of five amino acids in the extracellular domain of the Ret protein from amino acids 629 to 633 (UniProt.org). L629_L633del has been identified in the scientific literature (PMID: 28676824), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2024).
L633V	missense	unknown	RET L633V lies within the extracellular domain of the Ret protein (UniProt.org). L633V has been identified in the scientific literature (PMID: 30446652, PMID: 38378752), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
L633_A639del	deletion	unknown	RET L633_A639del results in the deletion of seven amino acids in the extracellular domain of the Ret protein from amino acids 633 to 639 (UniProt.org). E633_A639del has been identified in the scientific literature (PMID: 28209747), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
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, PMID: 34099825), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).	Y
L730Q	missense	unknown	RET L730Q lies within the protein kinase domain of the Ret protein (UniProt.org). L730Q has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
L730R	missense	unknown	RET L730R lies within the protein kinase domain of the Ret protein (UniProt.org). L730R has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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, PMID: 34099825), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).	Y
L760Q	missense	unknown	RET L760Q lies within the protein kinase domain of the Ret protein (UniProt.org). L760Q has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
L772M	missense	unknown	RET L772M lies within the protein kinase domain of the Ret protein (UniProt.org). L772M has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
L790F	missense	unknown	RET L790F lies within the protein kinase domain of the Ret protein (UniProt.org). L790F results in ligand-independent phosphorylation of Ret (PMID: 15184865, PMID: 23526464), however, also results in cell proliferation and transformation activity similar to wild-type Ret in cell culture (PMID: 21810974, PMID: 32546069), 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.
L870F	missense	unknown	RET L870F lies within the protein kinase domain of the Ret protein (UniProt.org). L870F has been identified in sequencing studies (PMID: 35304457), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2024).
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, Jun 2024).	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, Feb 2024).
L923I	missense	unknown	RET L923I lies within the protein kinase domain of the Ret protein (UniProt.org). L923I 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, Apr 2024).
L960R	missense	unknown	RET L960R lies within the protein kinase domain of the Ret protein (UniProt.org). L960R has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
M1008I	missense	unknown	RET M1008I lies within the protein kinase domain of the Ret protein (UniProt.org). M1008I has been identified in sequencing studies (PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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, PMID: 35181378), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2024).
M1064T	missense	unknown	RET M1064T lies within the cytoplasmic domain of the Ret protein (UniProt.org). M1064T does not affect the function of a concurrent activating RET mutation (C634R) in culture (PMID: 9502784), but has not been individually characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
M759I	missense	unknown	RET M759I lies within the protein kinase domain of the Ret protein (UniProt.org). M759I has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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 (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 (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.
N359T	missense	unknown	RET N359T lies within the extracellular domain of the Ret protein (UniProt.org). N359T has been identified in sequencing studies (PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
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 (PMID: 10921886), and therefore, is predicted to lead to a loss of Ret protein function.
P1047S	missense	no effect - predicted	RET P1047S lies within the cytoplasmic domain of the Ret protein (UniProt.org). P1047S results in proliferation, autophosphorylation, and Erk1/2 phosphorylation similar to wild-type Ret in culture (PMID: 29665843), and therefore, is predicted to have no effect on 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, Feb 2024).
P270L	missense	unknown	RET P270L lies within the Cadherin domain of the Ret protein (UniProt.org). P270L results in intracellular mislocalization near the endoplasmic reticulum and nucleus but phosphorylation of Ret and Erk similar to wild-type in culture (PMID: 26395553), and therefore, its effect on Ret protein function is unknown.
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, Feb 2024).
P622H	missense	unknown	RET P622H lies within the extracellular domain of the Ret protein (UniProt.org). P622H has not been characterized in the scientific literature and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
P695S	missense	unknown	RET P695S lies within the cytoplasmic domain of the Ret protein (UniProt.org). P695S has been identified in sequencing studies (PMID: 30664990, PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
P841L	missense	unknown	RET P841L lies within the protein kinase domain of the Ret protein (UniProt.org). P841L has been identified in sequencing studies (PMID: 27149842), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
P973L	missense	unknown	RET P973L lies within the protein kinase domain of the Ret protein (UniProt.org). P973L results in decreased Ret mRNA and protein levels and retains the ability to phosphorylate ERK in the presence of ligand in culture (PMID: 11438491), but has not been fully biochemically characterized and therefore, its effect on Ret protein function is unknown.
positive	unknown	unknown	RET positive indicates the presence of the RET gene, mRNA, and/or protein.
Q495*	nonsense	loss of function - predicted	RET Q495* results in a premature truncation of the Ret protein at amino acid 495 of 1114 (UniProt.org). Due to the loss of the protein kinase domain (UniProt.org), Q495* is predicted to lead to a loss of Ret protein function.
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, Feb 2024).
Q986*	nonsense	unknown	RET Q986* results in a premature truncation of the Ret protein at amino acid 986 of 1114 (UniProt.org). Q986* has been identified in sequencing studies (PMID: 27149842), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
R1013del	deletion	unknown	RET R1013del results in the deletion of an 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, Aug 2024).
R114H	missense	unknown	RET R114H lies within the extracellular domain of the Ret protein (UniProt.org). R114H has been identified in the scientific literature (PMID: 33827484, PMID: 34670378), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
R133C	missense	unknown	RET R133C lies within the extracellular domain of the Ret protein (UniProt.org). R133C has been identified in sequencing studies (PMID: 32284345, PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
R144H	missense	no effect - predicted	RET R144H lies within the extracellular domain of the Ret protein (UniProt.org). R144H results in phosphorylation of Ret and Erk similar to wild-type in cell culture (PMID: 26395553), and therefore, is predicted to have no effect on Ret protein function.
R177W	missense	unknown	RET R177W lies within the cadherin domain of the Ret protein (UniProt.org). R177W has been identified in sequencing studies (PMID: 34741450, PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
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 concurrent activating RET mutation (C634R) in culture (PMID: 9502784), and therefore, is predicted to lead to a loss of Ret protein function.
R417H	missense	unknown	RET R417H lies within the extracellular domain of the Ret protein (UniProt.org). R417H has been identified in sequencing studies (PMID: 27149842), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
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, Feb 2024).
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, PMID: 33827484), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
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, PMID: 33827484), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
R694Q	missense	no effect	RET R694Q lies within the cytoplasmic domain of the Ret protein (UniProt.org). R694Q fails to transform cells (PMID: 15472167) and results in Ret phosphorylation (PMID: 15472167, PMID: 26395553) and phosphorylation of Erk similar to wild-type Ret in cell culture (PMID: 26395553).
R721W	missense	unknown	RET R721W lies within the cytoplasmic domain of the Ret protein (UniProt.org). R721W has been identified in sequencing studies (PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
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, Feb 2024).
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, Apr 2024).
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, PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
R79W	missense	no effect - predicted	RET R79W lies within the extracellular domain of the Ret protein (UniProt.org). R79W results in phosphorylation of Ret and Erk similar to wild-type in cell culture (PMID: 26395553), and therefore, is predicted to have no effect on Ret protein function.
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 concurrent 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, Feb 2024).
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 concurrent 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, Feb 2024).
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 Mapk phosphorylation compared to wild-type Ret in culture (PMID: 29625052), and therefore, is predicted to lead to a 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, Feb 2024).
R969Q	missense	unknown	RET R969Q lies within the protein kinase domain of the Ret protein (UniProt.org). R969Q has been identified in sequencing studies (PMID: 27149842), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
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 concurrent 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).
S462L	missense	unknown	RET S462L lies within the extracellular domain of the Ret protein (UniProt.org). S462L has been identified in sequencing studies (PMID: 30446652), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
S649L	missense	unknown	RET S649L lies within the transmembrane domain of the Ret protein (UniProt.org). The functional effect of S649L is conflicting as it results in increased kinase activity and cell proliferation and moderate transforming activity in culture (PMID: 18322301), but in another study does not result in transforming activity in culture, leads to Ret pathway signaling similar to wild-type Ret in reporter assays (PMID: 21551259), and results in reduced ability to self-associate in culture (PMID: 23067224).
S649_V650insLLLL	insertion	unknown	RET S649_V650insLLLL results in the insertion of four amino acids in the helical domain of the Ret protein between amino acids 649 and 650 (UniProt.org).). S649_V650insLLLL has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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 concurrent 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, PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
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, Feb 2024).
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, Feb 2024).
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, Feb 2024).
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, Aug 2024).
T278N	missense	unknown	RET T278N lies within the extracellular domain of the Ret protein (UniProt.org). T278N has been identified in sequencing studies (PMID: 33827484, PMID: 33219105), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2024).
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, Feb 2024).
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.
T451M	missense	unknown	RET T451M lies within the extracellular domain of the Ret protein (UniProt.org). T451M has been identified in sequencing studies (PMID: 25425582, PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
T636M	missense	gain of function	RET T636M lies within the transmembrane domain of the Ret protein (UniProt.org). T636M results in increased Ret autophosphorylation and Erk1/2 and S6 phosphorylation, and increased proliferation, migration, and transformation in cultured cells (PMID: 25725622).
T742M	missense	unknown	RET T742M lies within the protein kinase domain of the Ret protein (UniProt.org). T742M has been identified in the scientific literature (PMID: 31712133, PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
T930K	missense	gain of function - predicted	RET T930K lies within the protein kinase domain of the Ret protein (UniProt.org). T930K results in Erk phosphorylation similar to wild-type Ret but cytokine-independent growth in culture (PMID: 32284345), and therefore, is predicted to lead to a gain of Ret protein function.
T930M	missense	no effect - predicted	RET T930M lies within the protein kinase domain of the Ret protein (UniProt.org). T930M results in Erk phosphorylation similar to wild-type Ret and does not result in cytokine-independent growth in culture (PMID: 32284345), and therefore, is predicted to have no effect on Ret protein function.
T930P	missense	gain of function - predicted	RET T930P lies within the protein kinase domain of the Ret protein (UniProt.org). T930P results in Erk phosphorylation similar to wild-type Ret but cytokine-independent growth in culture (PMID: 32284345), 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, Feb 2024).
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, Feb 2024).
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).
V351I	missense	unknown	RET V351I lies within the extracellular domain of the Ret protein (UniProt.org). V351I has been identified in sequencing studies (PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
V485L	missense	unknown	RET V485L lies within the extracellular domain of the Ret protein (UniProt.org). V485L has been identified in sequencing studies (PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
V591_G607del	deletion	unknown	RET V591_G607del results in the deletion of 17 amino acids in the extracellular domain of the Ret protein from amino acids 591 to 607 (UniProt.org). V591_G607del has been identified in the scientific literature (PMID: 36053791), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
V637M	missense	unknown	RET V637M lies within the transmembrane domain of the Ret protein (UniProt.org). V637M 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, Apr 2024).
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, Feb 2024).
V642F	missense	unknown	RET V642F lies within the transmembrane domain of the Ret protein (UniProt.org). V642F has been identified in sequencing studies (PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
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.
V706M	missense	unknown	RET V706M lies within the cytoplasmic domain of the Ret protein (UniProt.org). V706M has been identified in sequencing studies (PMID: 27683183, PMID: 30446652, PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).
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, PMID: 33161056), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).	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, Aug 2024).
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, Aug 2024).	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.
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, Feb 2024).	Y
V899_E902del	deletion	unknown	RET V899_E902del results in the deletion of four amino acids in the protein kinase domain of the Ret protein from amino acids 899 to 902 (UniProt.org). V899_E902del has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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, Feb 2024).
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.
Y1062C	missense	loss of function - predicted	RET Y1062C lies within the cytoplasmic domain of the Ret protein (UniProt.org). Y1062C results in reduced phosphorylation of Ret and Erk in cell culture (PMID: 26395553), and therefore, is predicted to lead to a loss of function of Ret protein function.
Y1062F	missense	loss of function	RET Y1062F lies within the cytoplasmic domain of the Ret protein (UniProt.org). Y1062F results in reduced phosphorylation of Ret and Erk (PMID: 26395553), decreased binding to Frs2 and Shc in cell culture (PMID: 11360177), decreased binding to Pkca and reduced activation of Pkc (PMID: 12771945), Mapk7 (Bmk1) (PMID: 11237712), and Rap1 in cell culture (PMID: 17210721), decreased PI3K/Akt and Mapk signaling in the context of RET C634Y expression in cell culture (PMID: 11390647, PMID: 10919641), and reduced signaling of the Ras-Mapk pathway in a reporter assay (PMID: 32062451).
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, increased Erk2 phosphorylation (PMID: 18248647, PMID: 36166639), and transformation in culture (PMID: 36166639).
Y791F	missense	unknown	RET Y791F lies within the protein kinase domain of the Ret protein (UniProt.org). Y791F results in ligand-independent kinase activity and activation of Stat3 signaling and is transforming in cell culture (PMID: 17209045, PMID: 15753368), but does not respond to growth factor stimulation in culture (PMID: 17209045) and results in enteric nervous system development similar to wild-type in a transgenic mouse model (PMID: 32275061), and therefore, its effect on Ret protein function is unknown.
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 (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, Feb 2024).	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, Jun 2024).
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, Aug 2024).	Y
EML4 - RET	fusion	gain of function - predicted	EML4-RET results from the fusion of EML4 and RET (PMID: 33082208), which results in increased Erk phosphorylation in cultured cells (PMID: 33848463), and therefore, is predicted to lead to a gain of protein function. EML4-RET has been identified in lung cancer (PMID: 33082208, PMID: 31485557, PMID: 30487236).

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