Gene Variant Detail

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Gene RET
Variant C634R
Impact List missense
Protein Effect gain of function
Gene Variant Descriptions 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).
Associated Drug Resistance

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Transcript NM_020975.5
gDNA chr10:g.43114500T>C
cDNA c.1900T>C
Protein p.C634R
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_020630.5 chr10:g.43114500T>C c.1900T>C p.C634R RefSeq GRCh38/hg38
NM_020975.5 chr10:g.43114500T>C c.1900T>C p.C634R RefSeq GRCh38/hg38
NM_020975 chr10:g.43114500T>C c.1900T>C p.C634R RefSeq GRCh38/hg38
NM_020630 chr10:g.43114500T>C c.1900T>C p.C634R RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET C634R Advanced Solid Tumor sensitive Pz-1 Preclinical - Cell line xenograft Actionable In a preclinical study, Pz-1 inhibited Ret signaling in transformed cells over expressing RET C634R and inhibited tumor growth in cell line xenografts models (PMID: 26126987). 26126987
RET C634R Advanced Solid Tumor sensitive Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and decreased growth of cells expressing RET C634R in culture (PMID: 17664273). 17664273
RET C634R Advanced Solid Tumor sensitive Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) inhibited RET kinase activity and proliferation in transformed cells expressing RET C634R in culture (PMID: 16507829). 16507829
RET C634R Advanced Solid Tumor sensitive Vandetanib Preclinical Actionable In a preclinical study, Caprelsa (vandetanib) inhibited RET phosphorylation and decreased growth of transformed cells expressing RET C634R in culture (PMID: 15184865). 15184865
RET C634R thyroid gland medullary carcinoma predicted - sensitive Sorafenib Phase II Actionable In a Phase II trial, Nexavar (sorafenib) treatment resulted in partial response in 50% (1/2) and stable disease in 50% (1/2) of patients with medullary thyroid carcinoma harboring RET C634R (PMID: 20368568). 20368568
RET C634R Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, transformed human cell lines expressing RET C634R demonstrated sensitivity to Iclusig (ponatinib) (PMID: 23811235). 23811235
RET C634R RET V804G Advanced Solid Tumor sensitive Vandetanib Preclinical Actionable In a preclinical study, transformed cell lines expressing Ret protein carrying both C634R and V804G mutations were more sensitive to Vandetanib induced inhibition of Ret activity than cells expressing Ret C634R alone 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 C634R RET Y806C Advanced Solid Tumor resistant Vandetanib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells co-expressing RET C634R and RET Y806C were resistant to treatment with Caprelsa (vandetanib) in culture (PMID: 19029224). 19029224
RET C634R RET Y806E Advanced Solid Tumor resistant Vandetanib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells co-expressing RET C634R and RET Y806E were resistant to treatment with Caprelsa (vandetanib) in culture (PMID: 19029224). 19029224
RET C634R RET Y806F Advanced Solid Tumor predicted - sensitive Vandetanib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells co-expressing RET C634R and RET Y806F in culture demonstrated inhibition of Ret phosphorylation and activity in kinase assays when treated with Caprelsa (vandetanib) (PMID: 19029224). 19029224
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 FDA approved 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... 32846061
RET mutant pheochromocytoma predicted - sensitive Sunitinib Case Reports/Case Series Actionable In a Phase II trial (SNIPP), a patient with pheochromocytoma harboring a RET mutation achieved a partial response to treatment with Sutent (sunitinib), and demonstrated a 64% reduction in tumor volume and has remained on treatment for over 7 years (PMID: 31105270). 31105270
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 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 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 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 C634X thyroid gland medullary carcinoma not applicable N/A Guideline Risk Factor Germline RET C634X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). detail...