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Gene RET
Variant V804L
Impact List missense
Protein Effect gain of function
Gene Variant Descriptions 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).
Associated Drug Resistance Y
Category Variants Paths

RET mutant RET act mut RET V804L

RET mutant RET V804X RET V804L

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Transcript NM_020975.6
gDNA chr10:g.43119548G>C
cDNA c.2410G>C
Protein p.V804L
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_020630.5 chr10:g.43119548G>C c.2410G>C p.V804L RefSeq GRCh38/hg38
NM_020975 chr10:g.43119548G>C c.2410G>C p.V804L RefSeq GRCh38/hg38
NM_020975.5 chr10:g.43119548G>C c.2410G>C p.V804L RefSeq GRCh38/hg38
NM_001406760.1 chr10:g.43119548G>C c.2410G>C p.V804L RefSeq GRCh38/hg38
NM_001406744.1 chr10:g.43119548G>C c.2410G>C p.V804L RefSeq GRCh38/hg38
NM_020630.7 chr10:g.43119548G>C c.2410G>C p.V804L RefSeq GRCh38/hg38
NM_001406759.1 chr10:g.43119548G>C c.2410G>C p.V804L RefSeq GRCh38/hg38
NM_020630 chr10:g.43119548G>C c.2410G>C p.V804L RefSeq GRCh38/hg38
NM_001406743.1 chr10:g.43119548G>C c.2410G>C p.V804L RefSeq GRCh38/hg38
NM_020975.6 chr10:g.43119548G>C c.2410G>C p.V804L RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET V804L Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, transformed human cell lines expressing RET V804L demonstrated sensitivity to Iclusig (ponatinib) (PMID: 23811235). 23811235
RET V804L Advanced Solid Tumor resistant Vandetanib Preclinical Actionable In a preclinical study, transformed cells expressing RET V804L demonstrated resistance to growth inhibition by Caprelsa (vandetanib) in culture (PMID: 15184865). 15184865
RET V804L Advanced Solid Tumor predicted - sensitive Pz-1 Preclinical Actionable In a preclinical study, Pz-1 inhibited Ret phosphorylation in transformed cells expressing RET V804L (PMID: 26126987). 26126987
RET V804L thyroid gland medullary carcinoma sensitive Selpercatinib Case Reports/Case Series Actionable In a Phase I/II trial (LIBRETTO-001), Retevmo (selpercatinib) treatment resulted in an objective response in three patients (3/5) and stable disease in two patients (2/5) with medullary thyroid cancer harboring RET V804L or RET V804M who had been treated previously (PMID: 32846061; NCT03157128). 32846061
RET V804L Advanced Solid Tumor predicted - sensitive APS03118 Preclinical - Biochemical Actionable In a preclinical study, APS03118 inhibited the enzymatic activity of RET V804L in an in vitro assay (J Clin Oncol 40, no. 16_suppl (June 1, 2022)). detail...
RET V804L Advanced Solid Tumor predicted - sensitive TY-1091 Preclinical - Biochemical Actionable In a preclinical study, TY-1091 inhibited activity in a cell line expressing RET V804L in culture (Cancer Res (2023) 83 (7_Supplement): 3419). detail...