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Gene	RET
Variant	E505_G506del
Impact List	deletion
Protein Effect	gain of function
Gene Variant Descriptions	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).
Associated Drug Resistance
Category Variants Paths	RET mutant RET act mut RET E505_G506del

Variant Reference Transcript
All Transcripts

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Transcript	NM_020975.6
gDNA	chr10:g.43111456_43111461delGAGGGG
cDNA	c.1513_1518delGAGGGG
Protein	p.E505_G506delEG
Source Database	RefSeq
Genome Build	GRCh38/hg38

Transcript	gDNA	cDNA	Protein	Source Database	Genome Build
NM_020630.7	chr10:g.43111456_43111461delGAGGGG	c.1513_1518delGAGGGG	p.E505_G506delEG	RefSeq	GRCh38/hg38
NM_001406791.1	chr10:g.43123687_43123692delCTGCTG	c.1513_1518delCTGCTG	p.L505_L506delLL	RefSeq	GRCh38/hg38
NM_001406785.1	chr10:g.43119669_43119674delGGGCCC	c.1514_1519delGGGCCC	p.R505_A506delRA	RefSeq	GRCh38/hg38
NM_020975.5	chr10:g.43111456_43111461delGAGGGG	c.1513_1518delGAGGGG	p.E505_G506delEG	RefSeq	GRCh38/hg38
NM_001406743.1	chr10:g.43111456_43111461delGAGGGG	c.1513_1518delGAGGGG	p.E505_G506delEG	RefSeq	GRCh38/hg38
NM_020630	chr10:g.43111456_43111461delGAGGGG	c.1513_1518delGAGGGG	p.E505_G506delEG	RefSeq	GRCh38/hg38
NM_001406783.1	chr10:g.43119677_43119682delACCATG	c.1513_1518delACCATG	p.T505_M506delTM	RefSeq	GRCh38/hg38
NM_001406777.1	chr10:g.43116687_43116692delAAGGCA	c.1514_1519delAAGGCA	p.K505_G506delKG	RefSeq	GRCh38/hg38
NM_001406792.1	chr10:g.43124905_43124910delTGGAAG	c.1513_1518delTGGAAG	p.W505_K506delWK	RefSeq	GRCh38/hg38
NM_001406788.1	chr10:g.43120171_43120176delTATGAA	c.1513_1518delTATGAA	p.Y505_E506delYE	RefSeq	GRCh38/hg38
NM_001406769.1	chr10:g.43114510_43114515delTGATCG	c.1514_1519delTGATCG	p.V505_I506delVI	RefSeq	GRCh38/hg38
NM_001406780.1	chr10:g.43119548_43119553delGTGGAG	c.1513_1518delGTGGAG	p.V505_E506delVE	RefSeq	GRCh38/hg38
NM_001406774.1	chr10:g.43114641_43114646delCAGGCC	c.1516_1521delCAGGCC	p.Q506_A507delQA	RefSeq	GRCh38/hg38
NM_001406794.1	chr10:g.43124905_43124910delTGGAAG	c.1513_1518delTGGAAG	p.W505_K506delWK	RefSeq	GRCh38/hg38
NM_001406770.1	chr10:g.43113597_43113602delGGGATT	c.1513_1518delGGGATT	p.G505_I506delGI	RefSeq	GRCh38/hg38
NM_001406759.1	chr10:g.43111456_43111461delGAGGGG	c.1513_1518delGAGGGG	p.E505_G506delEG	RefSeq	GRCh38/hg38
NM_001406771.1	chr10:g.43114551_43114556delCTGCTG	c.1513_1518delCTGCTG	p.L505_L506delLL	RefSeq	GRCh38/hg38
NM_001406761.1	chr10:g.43112220_43112225delCAAAGG	c.1515_1519+1delCAAAGG	p.K506_G507delKG	RefSeq	GRCh38/hg38
NM_001406763.1	chr10:g.43111456_43111461delGAGGGG	c.1513_1518delGAGGGG	p.E505_G506delEG	RefSeq	GRCh38/hg38
NM_001406784.1	chr10:g.43119644_43119649delAGCTCC	c.1516_1521delAGCTCC	p.S506_S507delSS	RefSeq	GRCh38/hg38
NM_001355216.1	chr10:g.43116723_43116728delTGCTGA	c.1514_1519delTGCTGA	p.M505_L506delML	RefSeq	GRCh38/hg38
NM_001406782.1	chr10:g.43119548_43119553delGTGGAG	c.1513_1518delGTGGAG	p.V505_E506delVE	RefSeq	GRCh38/hg38
NM_020975	chr10:g.43111456_43111461delGAGGGG	c.1513_1518delGAGGGG	p.E505_G506delEG	RefSeq	GRCh38/hg38
NM_001406760.1	chr10:g.43111456_43111461delGAGGGG	c.1513_1518delGAGGGG	p.E505_G506delEG	RefSeq	GRCh38/hg38
NM_001406790.1	chr10:g.43120171_43120176delTATGAA	c.1513_1518delTATGAA	p.Y505_E506delYE	RefSeq	GRCh38/hg38
NM_001406781.1	chr10:g.43119548_43119553delGTGGAG	c.1513_1518delGTGGAG	p.V505_E506delVE	RefSeq	GRCh38/hg38
NM_001406765.1	chr10:g.43111456_43111461delGAGGGG	c.1513_1518delGAGGGG	p.E505_G506delEG	RefSeq	GRCh38/hg38
NM_001406762.1	chr10:g.43112220_43112225delCAAAGG	c.1515_1519+1delCAAAGG	p.K506_G507delKG	RefSeq	GRCh38/hg38
NM_001406744.1	chr10:g.43111456_43111461delGAGGGG	c.1513_1518delGAGGGG	p.E505_G506delEG	RefSeq	GRCh38/hg38
NM_001406779.1	chr10:g.43119548_43119553delGTGGAG	c.1513_1518delGTGGAG	p.V505_E506delVE	RefSeq	GRCh38/hg38
NM_001406789.1	chr10:g.43120171_43120176delTATGAA	c.1513_1518delTATGAA	p.Y505_E506delYE	RefSeq	GRCh38/hg38
NM_020975.6	chr10:g.43111456_43111461delGAGGGG	c.1513_1518delGAGGGG	p.E505_G506delEG	RefSeq	GRCh38/hg38
NM_001406776.1	chr10:g.43116687_43116692delAAGGCA	c.1514_1519delAAGGCA	p.K505_G506delKG	RefSeq	GRCh38/hg38
NM_001406786.1	chr10:g.43119677_43119682delACCATG	c.1513_1518delACCATG	p.T505_M506delTM	RefSeq	GRCh38/hg38
NM_001406768.1	chr10:g.43112220_43112225delCAAAGG	c.1515_1519+1delCAAAGG	p.K506_G507delKG	RefSeq	GRCh38/hg38
NM_001355216.2	chr10:g.43116723_43116728delTGCTGA	c.1514_1519delTGCTGA	p.M505_L506delML	RefSeq	GRCh38/hg38
NM_020630.5	chr10:g.43111456_43111461delGAGGGG	c.1513_1518delGAGGGG	p.E505_G506delEG	RefSeq	GRCh38/hg38
NM_001406764.1	chr10:g.43112220_43112225delCAAAGG	c.1515_1519+1delCAAAGG	p.K506_G507delKG	RefSeq	GRCh38/hg38
NM_001406773.1	chr10:g.43114551_43114556delCTGCTG	c.1513_1518delCTGCTG	p.L505_L506delLL	RefSeq	GRCh38/hg38
NM_001406778.1	chr10:g.43116687_43116692delAAGGCA	c.1514_1519delAAGGCA	p.K505_G506delKG	RefSeq	GRCh38/hg38
NM_001406772.1	chr10:g.43114510_43114515delTGATCG	c.1514_1519delTGATCG	p.V505_I506delVI	RefSeq	GRCh38/hg38
NM_001406787.1	chr10:g.43119683_43119688delGGCGAC	c.1513_1518delGGCGAC	p.G505_D506delGD	RefSeq	GRCh38/hg38
NM_001406793.1	chr10:g.43124905_43124910delTGGAAG	c.1513_1518delTGGAAG	p.W505_K506delWK	RefSeq	GRCh38/hg38
NM_001406767.1	chr10:g.43113597_43113602delGGGATT	c.1513_1518delGGGATT	p.G505_I506delGI	RefSeq	GRCh38/hg38
NM_001406775.1	chr10:g.43116687_43116692delAAGGCA	c.1514_1519delAAGGCA	p.K505_G506delKG	RefSeq	GRCh38/hg38
NM_001406766.1	chr10:g.43113597_43113602delGGGATT	c.1513_1518delGGGATT	p.G505_I506delGI	RefSeq	GRCh38/hg38

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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... detail... 32846061
RET mutant	thyroid gland medullary carcinoma	sensitive	Selpercatinib	Guideline	Actionable	Retevmo (selpercatinib) is included in guidelines for patients with medullary thyroid carcinoma harboring RET mutations (NCCN.org).	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	Everolimus	Phase II	Actionable	In a Phase II 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; NCT01118065).	26294908
RET mutant	lung non-small cell carcinoma	predicted - sensitive	EP0031	Phase Ib/II	Actionable	In a Phase I/II trial (KL400-I/II-01), EP0031 treatment was well tolerated in non-small cell lung cancer (NSCLC) patients harboring RET mutations, and resulted in an objective response rate (ORR) of 63% (20/32, 1 complete response (CR)) and disease control rate (DCR) of 91% in pretreated patients, and an ORR of 76% (19/25, 1 CR) and DCR of 92% with median duration of response not reached in treatment-naive patients, and an overall CNS DCR of 100% (J Clin Oncol 41, 2023 (suppl 16; abstr 3007); NCT05265091).	detail...
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	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	Advanced Solid Tumor	predicted - sensitive	EP0031	Phase Ib/II	Actionable	In a Phase I/II trial (KL400-I/II-01), EP0031 treatment was well tolerated and demonstrated preliminary activity in patients with advanced solid tumors harboring mutations in RET, resulting in an objective response rate of 64%, with responses being observed in patients with non-small cell lung cancer, medullary thyroid cancer and pancreatic cancer (J Clin Oncol 41, 2023 (suppl 16; abstr 3007); NCT05265091).	detail...
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	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	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	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	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	Guideline	Actionable	Gavreto (pralsetinib) is included in guidelines (category 2B) for patients with medullary thyroid carcinoma harboring RET mutations (NCCN.org).	detail...
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...