Gene Variant Detail

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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

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Transcript NM_020975.5
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_020630 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
NM_020975.5 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

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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 predicted - sensitive Pz-1 Preclinical Actionable In a preclinical study, Pz-1 inhibited Ret phosphorylation in transformed cells expressing RET V804M (PMID: 26126987). 26126987
RET V804M thyroid gland medullary carcinoma sensitive Selpercatinib Phase I 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 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 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 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 C634R RET V804M Advanced Solid Tumor resistant Vandetanib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells co-expressing RET C634R and RET V804M were resistant to treatment with Caprelsa (vandetanib) in culture (PMID: 19029224). 19029224
RET V804M RET S904C thyroid gland medullary carcinoma not applicable N/A Guideline Risk Factor Compound germline RET V840M and S904C mutations result in multiple endocrine neoplasia, type 2B (MEN 2B), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET V804M RET Y806C thyroid gland medullary carcinoma not applicable N/A Guideline Risk Factor Compound germline RET V840M and Y806C mutations result in multiple endocrine neoplasia, type 2B (MEN 2B), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET V804M RET Y806C Advanced Solid Tumor decreased response Selpercatinib Preclinical - Biochemical Actionable In a preclinical study, transformed human cells expressing RET V804M and Y806C in cis were less sensitive to Retevmo (selpercatinib) in culture (PMID: 35304457). 35304457
RET V804M RET E805K thyroid gland medullary carcinoma not applicable N/A Guideline Risk Factor Compound germline RET V840M and E805K mutations result in multiple endocrine neoplasia, type 2B (MEN 2B), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...
RET V804M RET M918T lung adenocarcinoma resistant Alectinib Case Reports/Case Series Actionable In a clinical case study, a patient with lung adenocarcinoma initially treated with chemotherapy and immunotherapy was found to harbor KIF5B-RET, and was then treated with Alecensa (alectinib), which resulted in an intracranial response, but eventually led to further progression (PMID: 29912274; NCT03157128). 29912274
RET V804M RET M918T Advanced Solid Tumor predicted - sensitive Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, Retevmo (selpercatinib) inhibited cell growth and Ret phosphorylation in transformed cells expressing RET V804M and M918T in culture (PMID: 33161056). 33161056
RET V804M RET M918T thyroid gland medullary carcinoma predicted - sensitive Selpercatinib Case Reports/Case Series Actionable In a clinical case study, a patient with thyroid medullary cancer harboring RET M918T and RET V804M demonstrated an initial response to Retevmo (selpercatinib), which included a decrease in allelic fraction of RET M918T and RET V804M over 8 weeks and a radiographic response of nearly 54% post 6.9 months of treatment (PMID: 29912274; NCT03157128). 29912274
RET V804M RET M918T thyroid gland medullary carcinoma resistant Everolimus + Vandetanib Case Reports/Case Series Actionable In a clinical case study, a patient with thyroid medullary carcinoma harboring RET M918T progressed on multiple therapies, including Nexavar (sorafenib), Caprelsa (vandetanib), Cometriq (cabozantinib), MGCD-516 (sitravatinib), and RXDX-105 (CEP-32496), and upon progression with the combination therapy, Caprelsa (vandetanib) and Afinitor (everolimus), cell-free DNA testing revealed RET M918T and acquisition of a secondary drug resistant mutation, RET V804M (PMID: 29912274; NCT03157128). 29912274
RET V804M RET G810S RET L881V RET M918T thyroid gland medullary carcinoma predicted - resistant Selpercatinib Case Reports/Case Series Actionable In a clinical case study, a patient with hereditary medullary thyroid carcinoma harboring germline RET M918T demonstrated disease progression following an initial response to Retevmo (selpercatinib), and ctDNA sequencing revealed a decrease in RET L881V, but an increase in RET V804M and RET G810S (PMID: 31988000). 31988000
RET V804M RET G810C RET M918T Advanced Solid Tumor resistant Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing RET V804M, G810C, and M918T were resistant to Retevmo (selpercatinib) treatment in culture (PMID: 33161056). 33161056
RET V804M RET G810S RET M918T Advanced Solid Tumor resistant Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing RET V804M, G810S, and M918T were resistant to Retevmo (selpercatinib) treatment in culture (PMID: 33161056). 33161056
RET V804M RET Y806C RET M918T Advanced Solid Tumor predicted - resistant Selpercatinib Preclinical - Biochemical Actionable In a preclinical study, transformed human cells expressing RET M918T, V804M, and Y806C in cis were resistant to Retevmo (selpercatinib) in culture (PMID: 35304457). 35304457
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET act mut lung non-small cell carcinoma sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited RET phosphorylation and reduced viability of non-small cell lung cancer cells with RET activating mutations (Cancer Res April 15, 2013 73; 2084). detail...
RET mutant thyroid gland medullary carcinoma sensitive Selpercatinib Guideline Actionable Retevmo (selpercatinib) is included in guidelines for adult or pediatric patients 12 years or older with advanced medullary thyroid gland carcinoma harboring RET mutations (PMID: 31549998, PMID: 35491008; ESMO.org). 31549998 detail... 35491008
RET mutant thyroid gland medullary carcinoma sensitive Selpercatinib FDA approved - On Companion Diagnostic Actionable In a Phase I/II trial (LIBRETTO-001) that supported FDA approval, Retevmo (selpercatinib) treatment resulted in an objective response rate (ORR) of 69% (38/55), with five complete and 33 partial responses, in adult and pediatric patients of 12 years and older with medullary thyroid cancer harboring RET mutations who were previously treated, while patients who had not been previously treated demonstrated an ORR of 73% (64/88), with ten complete and 54 partial responses (PMID: 32846061; NCT03157128). detail... detail... 32846061
RET mutant lung non-small cell carcinoma unknown unspecified immune checkpoint inhibitor Clinical Study - Cohort Actionable In a retrospective clinical study, patients with non-small cell lung cancer harboring rare targetable drivers (RTD) (BRAF, ERBB2/3, RET, MET, ROS1, NTRK) who received immune checkpoint inhibitors (ICI) achieved longer median overall survival (mOS) (32 vs 13 mo, p=0.01) compared to those who did not receive ICI, mOS was 44.9 mo in a patient harboring RET mutation, although RTD type was not associated with OS in a univariate analysis (PMID: 30268448). 30268448
RET mutant thyroid gland medullary carcinoma sensitive Cabozantinib Phase III Actionable In a Phase III trial, Cometriq (cabozantinib) treatment resulted in improved progression free survival (60 vs 20 weeks) compared to placebo in thyroid medullary carcinoma patients harboring RET mutations (PMID: 27525386). 27525386
RET mutant colorectal cancer sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) demonstrated efficacy in RET mutant positive colorectal cancer cell lines (PMID: 23811235). 23811235
RET mutant cancer sensitive Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) inhibited wild-type RET and RET mutations to prevent cell proliferation in cell culture (PMID: 17664273). 17664273
RET mutant pheochromocytoma predicted - sensitive Sunitinib Case Reports/Case Series Actionable In a Phase II trial (SNIPP), a patient with pheochromocytoma harboring a germline RET mutation achieved a partial response to treatment with Sutent (sunitinib), and demonstrated a 64% reduction in tumor volume and remained on treatment for over 7 years (PMID: 31105270). 31105270
RET mutant thyroid gland medullary carcinoma sensitive Everolimus Phase II Actionable In a Phase II clinical trial, Afinitor (everolimus) treatment resulted in stable disease in 71% (5/7) of medullary thyroid cancer patients, including patients harboring RET mutations, with median progression-free survival of 33 weeks (PMID: 26294908). 26294908
RET mutant Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Iclusig (ponatinib) inhibited proliferation of cancer cell lines harboring RET mutations in cultured and in cell line xenograft models (PMID: 23526464). 23526464
RET mutant thyroid gland medullary carcinoma sensitive Pralsetinib Guideline Actionable Gavreto (pralsetinib) is included in guidelines for adult or pediatric patients 12 years or older with advanced or metastatic medullary thyroid gland carcinoma harboring RET mutations (PMID: 31549998, PMID: 35491008; ESMO.org). 31549998 detail... 35491008
RET mutant thyroid gland medullary carcinoma sensitive Pralsetinib FDA approved Actionable In a Phase I/II trial (ARROW) that supported FDA approval, Gavreto (pralsetinib) treatment was well-tolerated and resulted in an overall response rate (ORR) of 60% (3/55) in patients with advanced or metastatic medullary thyroid cancer harboring RET mutations who received prior treatments, ORR was 60% (32/53) in patients with prior therapies and 71% (15/21) in treatment-naive patients (PMID: 34118198; NCT03037385). 34118198 detail...
RET V804X thyroid gland medullary carcinoma sensitive Pralsetinib Phase Ib/II Actionable In a Phase I/II trial (ARROW), Gavreto (pralsetinib) treatment was well-tolerated, and resulted in an overall response rate (ORR) of 65% (51/79, 5% complete response, 59% partial response) in patients with advanced or metastatic medullary thyroid cancer harboring RET mutations, 4% of the patients harbored RET V804X (Ann Oncol. Vol 31, Supplement 4, S1084, Sep 1, 2020; NCT03037385). detail...
RET V804X thyroid gland medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET V804X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with increased risk of developing thyroid medullary carcinoma (NCCN.org). detail...