Gene Variant Detail

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Gene KIT
Variant Y823D
Impact List missense
Protein Effect gain of function
Gene Variant Descriptions KIT Y823D lies within the protein kinase domain of the Kit protein (UniProt.org). Y823D confers a gain of function on Kit, as indicated by constitutive phosphorylation of Kit in cultured cells (PMID: 14695343, PMID: 20633291).
Associated Drug Resistance

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Transcript NM_000222.2
gDNA chr4:g.54733175T>G
cDNA c.2467T>G
Protein p.Y823D
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_000222 chr4:g.54733175T>G c.2467T>G p.Y823D RefSeq GRCh38/hg38
XM_005265741 chr4:g.54733175T>G c.2467T>G p.Y823D RefSeq GRCh38/hg38
NM_000222.2 chr4:g.54733175T>G c.2467T>G p.Y823D RefSeq GRCh38/hg38
XM_005265741.1 chr4:g.54733175T>G c.2467T>G p.Y823D RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT Y823D Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited Kit autophosphorylation and proliferation of transformed cells expressing KIT Y823D in culture (PMID: 35194937). 35194937
KIT Y823D Advanced Solid Tumor sensitive Motesanib Diphosphate Preclinical - Cell culture Actionable In a preclinical study, Motesanib (AMG 706) inhibited KIT phosphorylation and growth of cells expressing KIT Y823D in culture (PMID: 20633291). 20633291
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor sensitive Regorafenib Preclinical - Pdx Actionable In a preclinical study, Stivarga (regorafenib) inhibited tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del and KIT Y823D (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor sensitive PLX9486 Preclinical - Pdx Actionable In a preclinical study, PLX9486 treatment decreased Mapk phosphorylation, inhibited proliferation, and reduced tumor growth and induced regression in a Gleevec (imatinib)-resistant patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del and Y823D (PMID: 30523507). 30523507
KIT W557_K558del KIT Y823D Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT Y823D demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D Advanced Solid Tumor decreased response Avapritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT Y823D demonstrated a decreased response to treatment with Ayvakit (avapritinib) compared to cells expressing KIT W557_K558del alone in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor sensitive Ponatinib Preclinical - Pdx & cell culture Actionable In a preclinical study, a patient derived GIST cell line co-harboring KIT W557_K558del and KIT Y823D demonstrated sensitivity to Iclusig (ponatinib) in a PDX model, resulting in complete tumor regression (PMID: 25239608). 25239608
KIT W557_K558del KIT Y823D Advanced Solid Tumor decreased response Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT Y823D demonstrated a decreased response to treatment with Qinlock (ripretinib) compared to cells expressing KIT W557_K558del alone in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D Advanced Solid Tumor resistant Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT Y823D demonstrated resistance to Sutent (sunitinb) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor sensitive Avapritinib Preclinical - Pdx Actionable In a preclinical study, Ayvakit (avapritinib) inhibited Kit phosphorylation and resulted in tumor regression in patient-derived xenograft models of Gleevec (imatinib mesylate)-resistant gastrointestinal stromal tumor harboring KIT W557_K558del and Y823D (PMID: 29093181). 29093181
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor sensitive AZD3229 Preclinical - Pdx Actionable In a preclinical study, AZD3229 inhibited Kit signaling and tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del and KIT Y823D (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT Y823D demonstrated resistance to Gleevec (imatinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D Advanced Solid Tumor predicted - sensitive Regorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT Y823D demonstrated sensitivity to treatment with Stivarga (regorafenib), but was decreased compared to cells expressing KIT W557_K558del alone in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor sensitive Ripretinib Preclinical - Pdx Actionable In a preclinical study, Qinlock (ripretinib) induced tumor regression in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del and KIT Y823D (PMID: 31085175). 31085175
KIT V559D KIT Y823D Advanced Solid Tumor no benefit Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing KIT Y823D and KIT V559D were insensitive to Sutent (sunitinib) in culture and in mouse models (PMID: 24205792). 24205792
KIT V559D KIT Y823D Advanced Solid Tumor no benefit Imatinib Preclinical Actionable In a preclinical study, Gleevec (imatinib) treatment in a mouse model with cells expressing KIT V559D and KIT Y823D resulted in shortened survival (PMID: 24205792). 24205792
KIT V559D KIT Y823D Advanced Solid Tumor sensitive Flumatinib Preclinical Actionable In a preclinical study, Flumatinib treatment in transformed cells co-expressing KIT N822K and KIT V559D demonstrated decreased cell proliferation and inhibition of Kit, Erk 1/2, and Stat3 phosphorylation in culture, and led to improved survival in mouse models (PMID: 24205792). 24205792
KIT exon 11 del KIT Y823D Advanced Solid Tumor predicted - sensitive THE-630 Preclinical - Cell culture Actionable In a preclinical study, THE-630 treatment inhibited growth of cells co-expressing a KIT exon 11 deletion and KIT Y823D in culture (Cancer Res 2021;81(13_Suppl):Abstract nr 1292). detail...
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT act mut gastrointestinal stromal tumor sensitive Pexidartinib Preclinical - Cell line xenograft Actionable In a preclinical study, PLX3397 inhibited growth of gastrointestinal stromal tumor cell lines harboring KIT activating mutations in culture and in cell line xenograft models (PMID: 24583793). 24583793
KIT act mut Advanced Solid Tumor sensitive PLX9486 Preclinical Actionable In a preclinical study, PLX9486 inhibited KIT mutations, including exon 17 mutations, and demonstrated in vivo and in vitro activity against tumors harboring KIT exon 17 mutations (Cancer Res February 1, 2016 76; IA32). detail...
KIT act mut gastrointestinal stromal tumor sensitive Cabozantinib Preclinical Actionable In a preclinical study, Cometriq (cabozantinib) decreased cell viability in imatinib-sensitive and resistant gastrointestinal stromal tumor (GIST) cell lines harboring KIT activating mutations in culture, and induced tumor regression in KIT-mutant GIST mouse models (PMID: 25836719). 25836719
KIT act mut skin melanoma sensitive Imatinib Guideline Actionable Gleevec (imatinib) is included in guidelines as second-line therapy for metastatic or unresectable cutaneous melanoma patients with KIT activating mutations (NCCN.org). detail...
KIT act mut gastrointestinal stromal tumor not applicable N/A Guideline Diagnostic KIT activating mutations aid the diagnosis of gastrointestinal stromal tumor (NCCN.org). detail...
KIT mutant melanoma predicted - sensitive Ripretinib Phase I Actionable In a Phase I trial, Qinlock (ripretinib) treatment demonstrated manageable safety and preliminary efficacy in patients with KIT-mutated melanoma, and led to an objective response rate of 23% (6/26, 1 complete and 5 partial responses), a median progression-free survival of 7.3 months, and a median duration of response of 7.4 months (Annals of Oncology 32 (2021): S896-S897; NCT02571036). detail...
KIT mutant gastrointestinal stromal tumor sensitive Imatinib + Infigratinib Preclinical - Pdx Actionable In a preclinical study, Truseltiq (infigratinib) and Gleevec (imatinib) combination treatment demonstrated enhanced antitumor activity in patient derived xenograft models of gastrointestinal stromal tumor harboring KIT mutations (PMID: 25673643). 25673643
KIT mutant gastrointestinal stromal tumor predicted - sensitive Avapritinib Phase I Actionable In a Phase I (NAVIGATOR) trial, Ayvakit (avapritinib) treatment resulted in an objective response rate of 13% (7/52, 7 partial responses) and a disease control rate of 63% (33/52) in patients with KIT-mutant gastrointestinal stromal tumor (The CTOS 2018 Annual Meeting, Nov 14-17, Rome Italy, Paper 012 3027631; NCT02508532). detail...
KIT mutant gastrointestinal stromal tumor predicted - sensitive Ripretinib Phase I Actionable In a Phase I trial, Qinlock (ripretinib) demonstrated preliminary safety and efficacy in patients with advanced solid tumors, including KIT-mutant gastrointestinal stromal tumor (GIST), with 1 patient harboring KIT exon 11 and 17 mutations demonstrating a partial response, and 7/7 KIT-mutant GIST patients demonstrating a partial metabolic response (EORTC-NCI-AACR 2016, Abs 7LBA). detail...
KIT mutant gastrointestinal stromal tumor predicted - sensitive Ripretinib Phase I Actionable In a Phase I trial, Qinlock (ripretinib) was well tolerated, resulted in an objective response in 11.3% (16/142, 16 partial responses) and stable disease in 61.3% (87/142) of patients with advanced gastrointestinal stromal tumor harboring KIT (exon 11, n=103; exon 9, n=26; other, n=6) or PDGFRA mutations (n=7), with a median progression-free survival of 5.6 months (PMID: 32804590; NCT02571036). 32804590
KIT mutant gastrointestinal stromal tumor not applicable N/A Clinical Study Diagnostic KIT mutations are used in the diagnosis of gastrointestinal stromal tumors (PMID: 25193432, PMID: 26276366, PMID: 25729899). 25193432 26276366 25729899
KIT mutant melanoma sensitive Nilotinib Phase II Actionable In a Phase II trial, Tasigna (nilotinib) treatment in patients with melanoma harboring KIT mutations resulted in an overall response rate of 26.2% (11/42), which included 11 patients with a partial response, a median duration of response of 7.1 months, and an overall survival of 18 months (PMID: 28327988; NCT01028222). 28327988
KIT mutant melanoma sensitive Nilotinib Phase II Actionable In a Phase II trial, Tasigna (nilotinib) treatment resulted in complete response in 4% (1/25), durable partial response in 16% (4/25), and stable disease in 56% (14/25) of melanoma patients harboring KIT mutations (PMID: 28843487; NCT01168050). 28843487
KIT exon17 Advanced Solid Tumor sensitive Avapritinib Preclinical Actionable In a preclinical study, Ayvakit (avapritinib) inhibited Kit phosphorylation and proliferation of various tumor cell lines harboring KIT exon 17 mutations in culture, and induced tumor regression in an allograft animal model (PMID: 29093181). 29093181
KIT exon17 gastrointestinal stromal tumor predicted - sensitive Pexidartinib + PLX9486 Phase I Actionable In a Phase I trial, PLX9486 and Pexidartinib (PLX3397) combination therapy demonstrated safety and preliminary efficacy, resulted in a partial response rate of 8.3% (1/12) and progression-free survival not yet reached in patients with advanced solid tumors, 11 of these patients had gastrointestinal stromal tumor that progressed on Gleevec (imatinib mesylate), and most harbored KIT exon 11 and exon 17 mutations (Journal of Clinical Oncology 36, no. 15_suppl (May 20 2018) 11509-11509; NCT02401815). detail...
KIT exon17 gastrointestinal stromal tumor sensitive Avapritinib Phase I Actionable In a Phase I trial, Ayvakit (avapritinib) demonstrated preliminary antitumor activity in gastrointestinal stromal tumor patients harboring KIT mutations, with reduced tumor burden in 38% (5/13) of patients, including 1 partial response and 4 stable diseases, and 3 of the 5 responding patients harbored KIT exon 17 mutations (EORTC-NCI-AACR 2016, Abs 6LBA). detail...
KIT exon17 gastrointestinal stromal tumor predicted - sensitive PLX9486 Phase I Actionable In a Phase I trial, PLX9486 demonstrated safety and preliminary efficacy, resulted in a progression-free survival of more than 24 weeks and partial response in 8.3% (2/24) of patients with advanced solid tumors, 20 of these patients had gastrointestinal stromal tumor that progressed on Gleevec (imatinib mesylate), and most harbored KIT exon 11 and exon 17 mutations (Journal of Clinical Oncology 36, no. 15_suppl (May 20 2018) 11509-11509; NCT02401815). detail...