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| Gene | VHL |
| Variant | E52fs |
| Impact List | frameshift |
| Protein Effect | loss of function - predicted |
| Gene Variant Descriptions | VHL E52fs results in a change in the amino acid sequence of the Vhl protein beginning at aa 52 of 213, likely resulting in premature truncation of the functional protein (UniProt.org). E52fs has not been characterized, however, due to the effects of other truncation mutations downstream of E52 (PMID: 14691445), is predicted to lead to a loss of Vhl protein function. |
| Associated Drug Resistance | |
| Category Variants Paths |
VHL mutant VHL inact mut VHL E52fs |
| Transcript | NM_000551.4 |
| gDNA | chr3:g.(10142000_10142001) |
| cDNA | c.(154_153) |
| Protein | p.E52fs |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| NM_000551.4 | chr3:g.(10142000_10142001) | c.(154_153) | p.E52fs | RefSeq | GRCh38/hg38 |
| NM_198156.2 | chr3:g.(10142000_10142001) | c.(154_153) | p.E52fs | RefSeq | GRCh38/hg38 |
| NM_198156 | chr3:g.(10142000_10142001) | c.(154_153) | p.E52fs | RefSeq | GRCh38/hg38 |
| NM_000551.3 | chr3:g.(10142000_10142001) | c.(154_153) | p.E52fs | RefSeq | GRCh38/hg38 |
| NM_198156.3 | chr3:g.(10142000_10142001) | c.(154_153) | p.E52fs | RefSeq | GRCh38/hg38 |
| NM_001354723.2 | chr3:g.(10142000_10142001) | c.(154_153) | p.E52fs | RefSeq | GRCh38/hg38 |
| NM_000551 | chr3:g.(10142000_10142001) | c.(154_153) | p.E52fs | RefSeq | GRCh38/hg38 |
| NM_001354723.1 | chr3:g.(10142000_10142001) | c.(154_153) | p.E52fs | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| VHL inact mut | renal cell carcinoma | predicted - sensitive | Everolimus | Case Reports/Case Series | Actionable | In a retrospective analysis from a Phase II clinical trial, patients with metastatic renal cell carcinoma treated with Afinitor (everolimus) had a trend towards improved in progression-free survival when stratified by the presence (median PFS=8.6 months, n=15) or absence (median PFS=5.5 months, n=16) of deleterious VHL mutations (PMID: 26951309). | 26951309 |
| VHL inact mut | retinal hemangioblastoma | sensitive | Belzutifan | Phase II | Actionable | In a Phase II trial, Welireg (belzutifan) treatment was safe and resulted in an overall response rate of 32% (16/50, 1 complete response, 15 partial responses) in patients with Von Hippel-Lindau disease-associated CNS hemangioblastoma harboring germline VHL mutations, 69% (11/16) of patients with retinal hemangioblastoma experienced improvement (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4555-4555; NCT03401788). | detail... |
| VHL inact mut | clear cell renal cell carcinoma | not applicable | N/A | Guideline | Risk Factor | Germline inactivating mutations in VHL result in von Hippel-Lindau (VHL) syndrome, which is associated with increased risk of developing clear cell renal cell carcinoma (NCCN.org). | detail... |
| VHL inact mut | renal cell carcinoma | predicted - sensitive | Alpha 2 Interferon + Bevacizumab | Clinical Study - Cohort | Actionable | In a retrospective analysis, VHL alterations did not impact overall survival or objective response in renal cell carcinoma patients treated with a VEGF-targeted therapy, including Avastin (bevacizumab) and Alpha 2 Interferon combination therapy, but were associated with a prolonged time to progression (PMID: 16827904). | 16827904 |
| VHL inact mut | clear cell renal cell carcinoma | conflicting | PT2399 | Preclinical - Pdx | Actionable | In a preclinical study, PT2399 had variable impact on tumor growth in clear cell renal cell carcinoma (ccRCC) cell line and patient-derived xenograft (PDX) models with defective VHL, with decreased tumor growth in a VHL-defective ccRCC PDX model and some VHL-defective ccRCC cell line xenograft models, and no tumor suppression in other cell line xenograft models (PMID: 27595393). | 27595393 |
| VHL inact mut | hemangioblastoma | sensitive | Belzutifan | Guideline | Actionable | Welireg (belzutifan) is included in guidelines for patients with Von Hippel-Lindau disease-associated CNS hemangioblastoma that do not require immediate surgery (NCCN.org). | detail... |
| VHL inact mut | hemangioblastoma | sensitive | Belzutifan | FDA approved | Actionable | In a Phase II trial (LITESPARK-004) that supported FDA approval, Welireg (belzutifan) treatment was safe and resulted in an objective response rate of 44% (22/61, 4 complete responses, 18 partial responses) in patients with Von Hippel-Lindau disease-associated CNS hemangioblastoma harboring germline VHL mutations, with a disease control rate of 90%, a median time to response of 5.4 months, and median progression-free survival not reached (J Clin Oncol 41, 2023 (suppl 16; abstr 2008); NCT03401788). | detail... detail... |
| VHL inact mut | renal cell carcinoma | sensitive | Pazopanib | Guideline | Actionable | Votrient (pazopanib) is included in guidelines as systemic therapy for patients with renal cell carcinoma associated with Von Hippel-Lindau disease (NCCN.org). | detail... |
| VHL inact mut | renal cell carcinoma | sensitive | Pazopanib | Phase II | Actionable | In a Phase II trial, Votrient (pazopanib) treatment resulted in an objective response rate of 42% (13/31, 13 partial responses) and stable disease in 58% of patients with Von Hippel-Lindau disease, with 75% (24/32) of the patients harboring confirmed VHL mutations; 52% (31/59, 2 complete and 29 partial responses) of target renal cell carcinomas responded to the treatment (PMID: 30236511; NCT01436227). | 30236511 |
| VHL inact mut | islet cell tumor | not applicable | N/A | Guideline | Risk Factor | Germline inactivating mutations in VHL result in von Hippel-Lindau (VHL) syndrome, which is associated with increased risk of developing pancreatic neuroendocrine tumors (NCCN.org). | detail... |
| VHL inact mut | renal cell carcinoma | sensitive | Belzutifan | Guideline | Actionable | Welireg (belzutifan) is included in guidelines for patients with Von Hippel-Lindau disease-associated renal cell carcinoma that do not require immediate surgery (NCCN.org). | detail... |
| VHL inact mut | renal cell carcinoma | sensitive | Belzutifan | FDA approved | Actionable | In a Phase II trial that supported FDA approval, Welireg (belzutifan) treatment was safe and resulted in a confirmed partial response (PR) in 36% (22/61) and unconfirmed PR in 11% (7/61) of patients with Von Hippel-Lindau disease-associated localized renal cell carcinoma harboring germline VHL mutations, median duration of response was not reached in responders (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4555-4555; NCT03401788). | detail... detail... |
| VHL inact mut | renal cell carcinoma | sensitive | Belzutifan | Guideline | Actionable | Welireg (belzutifan) is included in guidelines for patients with localized Von Hippel-Lindau disease-associated renal cell carcinoma harboring germline VHL mutations (PMID: 38788900; ESMO.org). | detail... 38788900 |
| VHL inact mut | renal cell carcinoma | no benefit | Apitolisib | Case Reports/Case Series | Actionable | In a retrospective analysis from a Phase II clinical trial, patients with metastatic renal cell carcinoma treated with Apitolisib (GDC-0980) had no difference in progression-free survival when stratified by the presence (n=5) or absence (n=17) of deleterious VHL mutations (PMID: 26951309). | 26951309 |
| VHL inact mut | pancreatic endocrine carcinoma | sensitive | Belzutifan | FDA approved | Actionable | In a Phase II trial that supported FDA approval, Welireg (belzutifan) treatment was safe and resulted in an overall response rate of 80% (16/20, 1 complete response, 15 partial responses) in patients with Von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors harboring germline VHL mutations (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4555-4555; NCT03401788). | detail... detail... |
| VHL mutant | renal cell carcinoma | sensitive | Everolimus | Phase I | Actionable | In a Phase I study, Afinitor (everolimus), as compared to Apitolisib (GDC-0980), resulted in a greater progression free survival and overall survival in patients with renal cell carcinoma harboring VHL mutations (J Clin Oncol 32:5s, 2014 (suppl; abstr 4525)). | detail... |
| VHL mutant | islet cell tumor | sensitive | Belzutifan | Guideline | Actionable | Welireg (belzutifan) is included in guidelines for patients with well-differentiated Grade 1/2 progressive pancreatic neuroendocrine tumors harboring germline VHL mutations (NCCN.org). | detail... |
| VHL mutant | renal cell carcinoma | predicted - sensitive | Sunitinib | Phase I | Actionable | In a Phase I trial, 33% (6/18) of renal cell carcinoma patients harboring a VHL mutation, as determined from archived patient specimens, demonstrated a partial response when treated with Sutent (sunitinib) (PMID: 22105611). | 22105611 |
| VHL mutant | renal cell carcinoma | no benefit | Unspecified VEGFR inhibitor | Clinical Study - Meta-analysis | Actionable | In a meta-analysis of 6 clinical studies, VHL mutation status was not associated with overall response rate (relative risk=1.47, p=0.20), progression-free survival (HR=1.02, p=0.91), or overall survival (HR=0.80, p=0.21) in a total of 633 patients with renal cell carcinoma who received anti-VEGF therapies (PMID: 28103578). | 28103578 |