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Gene | RET |
Variant | V804M |
Impact List | missense |
Protein Effect | gain of function |
Gene Variant Descriptions | 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). |
Associated Drug Resistance | Y |
Category Variants Paths |
RET mutant RET act mut RET V804M RET mutant RET V804X RET V804M |
Transcript | NM_020975.6 |
gDNA | chr10:g.43119548G>A |
cDNA | c.2410G>A |
Protein | p.V804M |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_020975.5 | chr10:g.43119548G>A | c.2410G>A | p.V804M | RefSeq | GRCh38/hg38 |
NM_020630.7 | chr10:g.43119548G>A | c.2410G>A | p.V804M | RefSeq | GRCh38/hg38 |
NM_001406760.1 | chr10:g.43119548G>A | c.2410G>A | p.V804M | RefSeq | GRCh38/hg38 |
NM_001406743.1 | chr10:g.43119548G>A | c.2410G>A | p.V804M | RefSeq | GRCh38/hg38 |
NM_020630.5 | chr10:g.43119548G>A | c.2410G>A | p.V804M | RefSeq | GRCh38/hg38 |
NM_020975.6 | chr10:g.43119548G>A | c.2410G>A | p.V804M | RefSeq | GRCh38/hg38 |
NM_001406744.1 | chr10:g.43119548G>A | c.2410G>A | p.V804M | RefSeq | GRCh38/hg38 |
NM_020630 | chr10:g.43119548G>A | c.2410G>A | p.V804M | RefSeq | GRCh38/hg38 |
NM_001406759.1 | chr10:g.43119548G>A | c.2410G>A | p.V804M | RefSeq | GRCh38/hg38 |
NM_020975 | chr10:g.43119548G>A | c.2410G>A | p.V804M | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
RET V804M | Advanced Solid Tumor | sensitive | Ponatinib | Preclinical | Actionable | In a preclinical study, transformed human cell lines expressing RET V804M demonstrated sensitivity to Iclusig (ponatinib) (PMID: 23811235). | 23811235 |
RET V804M | Advanced Solid Tumor | sensitive | Sorafenib | Preclinical | Actionable | In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and decreased growth of transformed cells expressing RET V804M in culture (PMID: 16507829). | 16507829 |
RET V804M | Advanced Solid Tumor | resistant | Vandetanib | Preclinical | Actionable | In a preclinical study, transformed cells expressing RET V804M demonstrated resistance to growth inhibition by Caprelsa (vandetanib) in culture (PMID: 15184865). | 15184865 |
RET V804M | Advanced Solid Tumor | predicted - sensitive | Pz-1 | Preclinical | Actionable | In a preclinical study, Pz-1 inhibited Ret phosphorylation in transformed cells expressing RET V804M (PMID: 26126987). | 26126987 |
RET V804M | medullary thyroid carcinoma | sensitive | Selpercatinib | Case Reports/Case Series | Actionable | In a Phase I trial, Retevmo (selpercatinib) treatment resulted in partial response in a thyroid medullary cancer patient harboring RET V804M (J Clin Oncol 36, 2018 (suppl; abstr 102); NCT03157128). | detail... |
RET V804M | medullary thyroid 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 V804M or RET V804L who were previously treated (PMID: 32846061; NCT03157128). | detail... 32846061 |
RET V804M | Advanced Solid Tumor | predicted - sensitive | APS03118 | Preclinical - Biochemical | Actionable | In a preclinical study, APS03118 inhibited the enzymatic activity of RET V804M in an in vitro assay, inhibited Ret phosphorylation in cells expressing RET V804M in culture, and inhibited tumor growth in cell line xenograft models expressing RET V804M (J Clin Oncol 40, no. 16_suppl (June 1, 2022)). | detail... |
RET V804M | Advanced Solid Tumor | predicted - sensitive | TY-1091 | Preclinical - Biochemical | Actionable | In a preclinical study, TY-1091 inhibited activity in a cell line expressing RET V804M in culture (Cancer Res (2023) 83 (7_Supplement): 3419). | detail... |
RET V804M | Advanced Solid Tumor | predicted - sensitive | FHND5071 | Preclinical - Cell culture | Actionable | In a preclinical study, FHND5071 inhibited Ret phosphorylation and proliferation in cells expressing RET V804M in culture (Cancer Res (2023) 83 (8_Supplement): LB330). | detail... |