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| Gene | KIT |
| Variant | D816H |
| Impact List | missense |
| Protein Effect | gain of function |
| Gene Variant Descriptions | KIT D816H lies within the tyrosine kinase domain region 2 (exon 17) of the Kit protein (PMID: 19164557). D816H results in increased kinase activity, constitutive Kit phosphorylation, activation of Stat3 signaling, and transformation of cultured cells (PMID: 10362788, PMID: 11494148), and confers resistance to some Kit inhibitors (PMID: 25239608). |
| Associated Drug Resistance | Y |
| Category Variants Paths |
KIT mutant KIT act mut KIT D816H KIT mutant KIT exon17 KIT D816X KIT D816H |
| Transcript | NM_000222.3 |
| gDNA | chr4:g.54733154G>C |
| cDNA | c.2446G>C |
| Protein | p.D816H |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| NM_001093772.1 | chr4:g.54733166G>C | c.2446G>C | p.D816H | RefSeq | GRCh38/hg38 |
| XM_005265741 | chr4:g.54733154G>C | c.2446G>C | p.D816H | RefSeq | GRCh38/hg38 |
| NM_000222.3 | chr4:g.54733154G>C | c.2446G>C | p.D816H | RefSeq | GRCh38/hg38 |
| NM_001385292.1 | chr4:g.54733166G>C | c.2446G>C | p.D816H | RefSeq | GRCh38/hg38 |
| XM_017008179 | chr4:g.54733166G>C | c.2446G>C | p.D816H | RefSeq | GRCh38/hg38 |
| NM_000222 | chr4:g.54733154G>C | c.2446G>C | p.D816H | RefSeq | GRCh38/hg38 |
| NM_001093772.2 | chr4:g.54733166G>C | c.2446G>C | p.D816H | RefSeq | GRCh38/hg38 |
| NM_001385290.1 | chr4:g.54733154G>C | c.2446G>C | p.D816H | RefSeq | GRCh38/hg38 |
| NM_000222.2 | chr4:g.54733154G>C | c.2446G>C | p.D816H | RefSeq | GRCh38/hg38 |
| NM_001093772 | chr4:g.54733166G>C | c.2446G>C | p.D816H | RefSeq | GRCh38/hg38 |
| XM_005265741.1 | chr4:g.54733154G>C | c.2446G>C | p.D816H | RefSeq | GRCh38/hg38 |
| XM_017008179.1 | chr4:g.54733166G>C | c.2446G>C | p.D816H | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| KIT act mut | skin melanoma | sensitive | Dasatinib | Guideline | Actionable | Sprycel (dasatinib) 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 | 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 | 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 | melanoma | predicted - sensitive | Regorafenib | Case Reports/Case Series | Actionable | In a clinical case study, Stivarga (regorafenib) treatment demonstrated safety and preliminary activity in patients with melanoma harboring activating mutations in KIT, resulting in an overall response rate of 100% (7/7, 1 complete and 6 partial responses), with median duration of response and median progression-free survival not reached and response ongoing in 4 patients at a median follow-up of 43 weeks (Ann Oncol (2024) 35 (suppl_2): S743-S744). | detail... |
| KIT act mut | skin melanoma | sensitive | Ripretinib | Guideline | Actionable | Qinlock (ripretinib) 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 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 | skin melanoma | sensitive | Nilotinib | Guideline | Actionable | Tasigna (nilotinib) 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 | 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 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 | 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 | 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 | 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 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 | 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 9.1 months (PMID: 35753087; NCT02571036). | 35753087 |
| 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 D816X | systemic mastocytosis | not applicable | N/A | Guideline | Diagnostic | Activating mutations at codon 816 of KIT aid in the diagnosis of systemic mastocytosis (NCCN.org). | detail... |
| KIT exon17 | melanoma | not predictive | Pembrolizumab | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Toripalimab (JS001) resulted in a median disease-free survival of 33 months in melanoma patients harboring KIT mutations in either exon 11 (64.8%), exon 13 (17.6%), or exon 17 (17.6%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p=0.200) (PMID: 37403699). | 37403699 |
| 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 | mucosal melanoma | predicted - sensitive | Avapritinib | Case Reports/Case Series | Actionable | In a clinical case study, Ayvakit (avapritinib) resulted in a reduction of the metastatic lesions, including brain metastases, in a patient with mucosal melanoma harboring a KIT exon 17 mutation (PMID: 35820244). | 35820244 |
| KIT exon17 | melanoma | sensitive | Regorafenib | Case Reports/Case Series | Actionable | In a Phase II trial, second or later-line Stivarga (regorafenib) treatment resulted in a disease control rate of 73.9% (17/23, 2 complete responses, 5 partial responses), an objective response rate of 30.4% (7/23), and median overall survival (mOS) of 21.5 months in patients with melanoma harboring KIT exon 9, 11, 13, or 17 mutations, and improved mOS in patients with non-exon 11 mutations compared to patients with exon 11 mutations (24.9 mo vs 18.3 mo, P=0.042) (PMID: 37741071; NCT02501551). | 37741071 |
| 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... |
| KIT exon17 | melanoma | not predictive | Toripalimab-tpzi | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Loqtorz (toripalimab-tpzi) resulted in a median disease-free survival of 33 months in melanoma patients harboring KIT mutations in either exon 11 (64.8%), exon 13 (17.6%), or exon 17 (17.6%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p=0.200) (PMID: 37403699). | 37403699 |