Summary
Autosomal-dominant (AD) pathogenic/likely pathogenic (P/LP) variants in von Hippel-Lindau (VHL) gene cause VHL disease. We characterize VHL variants and disease phenotypes in Black/African American (AA) patients, a demographic that has not been thoroughly studied. Black/AA patients undergoing germline genetic testing at a CLIA-certified commercial laboratory from November 2014 to March 2022 and carrying a P/LP AD VHL gene variant were identified. Personal and family histories were obtained from test requisition forms, and patients were categorized into VHL disease subtypes: type 1, type 2A, type 2B, and type 2C. Patients with a personal or family history of cancer but no lesions typical of VHL disease were categorized as “unclassified.” Patients with an incomplete personal or family history available were noted as “unknown.” Final analysis included 38 patients. Among the cohort’s personal cancer history, hemangioblastoma and pheochromocytoma were most prevalent (16%). Among the cohort’s family cancer history, renal cell carcinoma was most prevalent (8%). Type 1 was the most common VHL disease class recorded (34%). Substitution variants were most common (76%); p.Arg167Trp (c.499C>T) was the most common substitution (8%). Unique variants in Black/AA patients include p.Pro81Leu (c.242C>T), p.Leu129Pro (c.386T>C), p.Asp121Val (c.362A>T), p.His110Profs∗49 (c.329del), and p.Arg82His (c.245G>A). This dataset informs future research on VHL disease and treatment in Black/AA populations.
Keywords: von Hippel Lindau disease, VHL, African American, hereditary cancer, germline testing, genetic testing, renal cell carcinoma, pheochromocytoma, belzutifan, health disparities
This study characterizes germline VHL variants in Black/African American patients, an underrepresented population in hereditary cancer research. By defining disease characteristics and unique variants and highlighting challenges in genetic testing, these findings underscore the need for inclusive research to ensure equitable access to emerging targeted therapies.
Introduction
von Hippel-Lindau disease (VHL; OMIM: 193300) is a rare autosomal-dominant (AD) hereditary cancer syndrome with an incidence of 1 in 36,000 individuals and reduced penetrance.1 It is characterized by increased risk for retinal and craniospinal hemangioblastomas, pheochromocytomas, paragangliomas, renal cell carcinoma (RCC), endolymphatic sac tumors, epididymal/broad ligament cystadenomas, and pancreatic neuroendocrine tumors (pNETs).2,3 It can present in the first decade of life and affects all populations regardless of race or sex.2
VHL disease results from pathogenic/likely pathogenic (P/LP) germline variants in the VHL gene (HGNC: 12687). It is categorized as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma). Type 2 disease is further divided into 2A (low RCC risk), 2B (high RCC risk), and 2C (pheochromocytoma only).4 Genotype-phenotype correlations are well established: frameshift and nonsense variants are typically associated with type 1 disease, while missense variants affecting codon 167 are linked to type 2 disease.5
Most reported germline VHL variants have been defined in non-Hispanic White and Asian populations, with limited data on Black/African American (AA) patients due to the disease’s rarity.4˒6,7,8,9,10 With the expansion of germline genetic testing (GGT) and the approval of belzutifan for VHL disease, germline pathogenic VHL variants are now considered clinically actionable.11,12 In light of these advances, we aimed to characterize AD VHL variants and genotype-phenotype correlations in a cohort of Black/AA participants undergoing GGT for personal and/or family history of cancer.
Material and methods
Study population
This retrospective study included participants who underwent GGT from November 2014 to March 2022 for a personal and/or family history of cancer through a single CLIA-certified commercial laboratory (Invitae Corporation, San Francisco, CA). Black/AA patients carrying a P/LP germline VHL variant were included. This cohort study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. This study was conducted in accordance with the recommendations of the Wayne State University institutional review board (IRB). All participants’ clinical and demographic data, as entered by ordering clinicians on test requisition forms, were de-identified prior to analysis to comply with WCG protocol 1167406, which permits study and publication of de-identified data.
Clinical, individual, and family histories
Demographic data and clinical histories, including personal and family cancer history, were ascertained from clinician-completed test requisition forms. Race and ethnicity were based on clinician-reported data; participants without a documented race or with an ethnicity listed as “unknown” or “other” were excluded. Family history included first-degree relatives (father, mother, siblings, and children) and extended-degree relatives (grandparents, uncles, aunts, and cousins) as reported by the participant or recorded in their medical record.
Detection and interpretation of genetic variants
GGT was performed at Invitae Corporation, as previously described.13 VHL P/LP variants were identified through single-gene testing or multigene panels (range 2–157 genes). The VHL sequence analysis covers all coding exons and 10 or more base pairs of adjacent intronic sequences. All VHL variants were classified using the Sherloc framework as pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign, or benign.14 Since AD VHL variants cause VHL disease and autosomal-recessive VHL variants cause congenital polycythemia, only participants with AD P/LP variants were included in the final analysis.
Categorization of VHL disease
Participants were categorized by VHL disease type using personal and family history. Type 1 disease included those without a personal or family history of pheochromocytoma. Type 2 disease included those with a personal or family history of pheochromocytoma. Type 2 disease is further categorized as type 2A (pheochromocytoma without a personal or family history of RCC), type 2B (pheochromocytoma with a personal or family history of RCC), and type 2C (pheochromocytoma without other VHL-specific lesions, such as hemangioblastoma or RCC). Participants who had a personal or family history of cancer but no specific lesions typical of VHL disease noted (which includes central nervous system [CNS] hemangioblastomas, retinal angiomas, RCC, pheochromocytomas, pNETs, pancreatic serous cystadenoma, middle ear endolymphatic sac tumor, and papillary cystadenomas of the epididymis and/or broad ligament) were categorized as “unclassified.” Participants with incomplete personal or family histories were noted as unknown.
Statistical analysis
Data were descriptively summarized by count (percentage) and median (range) for categorical and continuous variables, respectively. No formal hypothesis testing was performed.
Results
A total of 481,596 participants underwent GGT during the study period. Of these, 441 carried AD VHL P/LP variants, of whom 38 participants self-identified as Black/AA and were included in the final analysis.
Table 1 summarizes baseline demographic characteristics. Of the 38 participants, 29 (76%) reported as Black/AA only and 9 (24%) as Black/AA plus another ethnicity (Mediterranean and White [n = 4], White [n = 2], Asian [n = 2], and Hispanic [n = 1]). The cohort comprised 21 females (55%). The median genetic testing age was 29 years. Substitution variants were the most common VHL variant type (n = 29, 76%), followed by insertions or deletions (indels; n = 7, 19%) and copy-number variants (CNVs; n = 2, 5%). Eleven participants (29%) reported a family history of VHL disease, while most participants had incomplete or unknown family histories (n = 20, 53%). Type 1 VHL disease was the most common (n = 13, 34%), followed by type 2B (n = 4, 11%) and type 2C (n = 2, 5%). No participants were classified as type 2A. Two participants (5%) were unclassified due to unrelated cancers (colorectal cancer or invasive ductal breast carcinoma). Seventeen (45%) were categorized as unknown because of insufficient clinician-reported data. Personal and family histories by race are further detailed in Table 2. Hemangioblastoma and pheochromocytoma were most frequent in the index patient population (n = 6, 16%). Family history of RCC was the most common cancer occurrence (n = 3, 8%).
Table 1.
Baseline characteristics
| All participants (N = 38) | |
|---|---|
| Age at accession, median (range) | 29 (1,62) |
| Gender, no. (%) | |
| Female | 21 (55) |
| Male | 17 (45) |
| Ethnicity, no. (%) | |
| Black/African American only | 29 (76) |
| Black/African American plus another ethnicity | 9 (24) |
| Another ethnicity subtypes, no. (%) | |
| Mediterranean and White | 4 (11) |
| White | 2 (5) |
| Asian | 2 (5) |
| Hispanic, Native American, and White | 1 (3) |
| VHL variant type, no. (%) | |
| Substitution | 29 (76) |
| Indel | 7 (19) |
| CNV | 2 (5) |
| Family cancer history, no. (%) | |
| Yes | 8 (21) |
| No | 10 (26) |
| Unknown | 20 (53) |
| Family VHL history, no. (%) | |
| Yes | 11 (29) |
| No | 7 (18) |
| Unknown | 20 (53) |
| No. of genes, median (range) | 5.5 (1, 85) |
| VHL disease class type, no. (%) | |
| Type 1 | 13 (34) |
| Type 2A | 0 (0) |
| Type 2B | 4 (11) |
| Type 2C | 2 (5) |
| Unknown | 17 (45) |
| Unclassified | 2 (5) |
Table 2.
Distribution of personal and family history of cancer
| Cancer type, no. (%) | All (N = 38) |
|---|---|
| Personal history cancer type | |
| Hemangioblastoma | 6 (16) |
| Pheochromocytoma | 6 (16) |
| Paraganglioma | 5 (13) |
| Pancreas | 5 (13) |
| Kidney | 4 (11) |
| Adrenal | 4 (11) |
| Colon | 1 (3) |
| Breast | 1 (3) |
| Lung | 1 (3) |
| Family history cancer type | |
| Kidney | 3 (8) |
| Breast | 2 (5) |
| Pancreas | 1 (3) |
| Pheochromocytoma | 1 (3) |
| Hemangioblastoma | 1 (3) |
| Colon | 1 (3) |
| Prostate | 1 (3) |
| Lung | 1 (3) |
| Liver | 1 (3) |
| Gastrointestinal stronal tumor (GIST) | 1 (3) |
| Unknown site | 1 (3) |
Prevalence and spectrum of germline VHL sequence variation
Table 3 describes the characteristics of individual participants represented in this study. Indel p.Asn150Tyrfs∗23 (c.448_449del) was the most common variant overall (n = 6, 16%). Substitution variants occurred in 76% of the cohort (n = 29), predominantly among participants identifying solely as Black/AA (n = 26, 68%). Codon 167 substitution variants were of special interest and represented 11% of the cohort (n = 4). For CNVs, deletion of exon 3 and deletion of the entire coding sequence were seen with equal frequency (n = 1, 3%). The most common substitution variants were p.Arg167Trp (c.499C>T) (n = 3, 8%), followed by p.Pro81Leu (c.242C>T), p.Gln73∗ (c.217C>T), p.Asp126Asn (c.376G>A), and splice acceptor (each n = 2, 5%).
Table 3.
Individual participant characteristics
| Patient ID | Gender | Age | Ethnicity | VHL variant NM_000551.3 | VHL effects | Personal history | Family history | Disease type |
|---|---|---|---|---|---|---|---|---|
| 102 | male | 18 | AA | c.242C>T | p.Pro81Leu | PPGL | NK | 1 |
| 103 | female | 34 | AA | c.341-2A>G | splice acceptor | RCC, Pheo, HB | RCC, HB | 2B |
| 114 | female | 49 | AA | c.242C>T | p.Pro81Leu | NK | VHL | NK |
| 116 | male | 28 | AA | c.464-?_∗3705+?del | del (exon 3) | VHL; RCC, Pheo; HB | NK | 2B |
| 164 | female | 44 | AA | c.262T>A | p.Trp88Arg | VHL; HB; spinal cyst; PC | RCC | 1 |
| 368 | female | 17 | AA | c.472C>G | p.Leu158Val | NK | VHL | NK |
| 432 | male | 32 | A; AA | c.320G>C | p.Arg107Pro | NK | NK | NK |
| 454 | male | 17 | AA; H; NA; W | c.461C>T | p.Pro154Leu | HB | NK | 1 |
| 482 | male | 43 | AA | c.376G>A | p.Asp126Asn | bladder PPGL | NK | 1 |
| 583 | female | 27 | AA | c.341−2A>G | splice acceptor | VHL; PC; renal cysts | VHL | 1 |
| 614 | female | 40 | AA | c.376G>A | p.Asp126Asn | NK | BC; HCC; LC | NK |
| 642 | male | 4 | AA; W | c.448_449del | p.Asn150Tyrfs∗23 | NK | VHL | NK |
| 659 | male | 25 | AA; M; W | c.448_449del | p.Asn150Tyrfs∗23 | NK | VHL | NK |
| 673 | female | 27 | AA; W | c.448_449del | p.Asn150Tyrfs∗23 | NK | VHL | NK |
| 685 | female | 3 | AA; M; W | c.448_449del | p.Asn150Tyrfs∗23 | NK | VHL | NK |
| 721 | female | 20 | AA; M; W | c.448_449del | p.Asn150Tyrfs∗23 | NK | VHL | NK |
| 723 | female | 5 | AA; M; W | c.448_449del | p.Asn150Tyrfs∗23 | NK | VHL | NK |
| 744 | female | 28 | AA | c.245G>A | p.Arg82His | Pheo | NK | 2C |
| 756 | male | 50 | AA | c.217C>T | p.Gln73∗ | RCC; PC | NK | 1 |
| 829 | male | 32 | AA | c.233A>G | p.Asn78Ser | HB, PC, adrenal cyst | NK | 1 |
| 860 | female | 29 | AA | c.492G>T | p.Gln164His | adrenal cyst | prostate cancer | 1 |
| 959 | female | 38 | AA | c.340+790G>A | intronic | BC | NK | UC |
| 1018 | male | 62 | AA | c.362A>T | p.Asp121Val | NK | NK | NK |
| 1049 | female | 60 | AA | c.499C>T | p.Arg167Trp | NK | NK | NK |
| 1310 | female | 27 | AA | c.213-?_∗3705+?del | del (entire coding sequence) | adrenal mass; PC | cancer (NK site) | 1 |
| 1490 | male | 39 | AA | c.500G>A | p.Arg167Gln | Pheo; PPGL; adrenal and renal mass | NK | 2B |
| 1581 | male | 71 | AA | c.429C>T | silent | VHL | NK | 1 |
| 1847 | female | 25 | AA | c.499C>T | p.Arg167Trp | NK | NK | NK |
| 1853 | female | 1 | AA | c.499C>T | p.Arg167Trp | NK | VHL | NK |
| 1854 | male | 27 | AA | c.482G>A | p.Arg161Gln | Pheo | VHL; Pheo | 2B |
| 2072 | male | 55 | AA | c.217C>T | p.Gln73∗ | HB | RCC, PAC | 1 |
| 2176 | male | 9 | AA | c.473T>C | p.Leu158Pro | NK | NK | NK |
| 2233 | male | 28 | AA | c.386T>C | p.Leu129Pro | Pheo | NK | 2C |
| 2400 | female | 1 | AA | c.277G>C | p.Gly93Arg | NK | NK | NK |
| 2515 | female | 29 | AA | c.239G>T | p.Ser80Ile | pancreatic PPGL; lung metastasis | NK | 1 |
| 2679 | male | 46 | AA | c.161T>G | p.Met54Arg | CRC | CRC; BC; GIST | UC |
| 2800 | female | 62 | AA | c.329del | p.His110Profs∗49 | RCC | NK | 1 |
| 2826 | female | 34 | AA | c.598C>T | p.Arg200Trp | NK | NK | NK |
AA, Black/African American; PPGL, paraganglioma; NK, unknown; RCC, renal cell carcinoma; Pheo, pheochromocytoma; HB, hemangioblastoma; PC, pancreatic cyst; H, Hispanic; NA, Native American; W, White; BC, breast cancer; UC, unclassified; HCC, hepatocellular carcinoma; LC, lung cancer; M, Mediterranean; PAC, pancreatic cancer; CRC, colorectal cancer; GIST, gastrointestinal stromal tumor.
Discussion
Our study provides a description of VHL variants with genotype-phenotype correlation in Black/AA patients undergoing GGT for personal or family history of cancer. VHL disease has been extensively described in White and Asian patients, with sparse research on Black/AA patients.1,4,5,6,7,8,9,10 In recent years, Ganner et al. provided the largest study of VHL variants in 1,350 participants across 40 centers worldwide.13 However, the race distribution of participants in this large study was not described.13 Additionally, individual VHL variants are associated with specific phenotypic and penetrance features, suggesting that generalizations about phenotypes should be made with caution.1,4,5,6,7,8,9,10,13 Our study provides patient-level data of a cohort of Black/AA participants with germline VHL variants who are otherwise under-represented in clinical studies.
Most participants in our study carried missense substitution variants (76%) rather than indel variants (19%) and CNVs (5%). This is in line with findings from Ganner et al., who found missense variants in 67.2% and truncation/deletion variants in 32.8% of the participants.13 The most common variant overall was indel p.Asn150Tyrfs∗23, occurring in 16% of our cohort. Personal history of malignancy was unknown in these participants. However, all of these participants were known to have a family history of VHL disease and are expected to have type 1 disease as seen in the database by Nordstrom-O’Brian et al. for truncating mutations at codon 150,4 We report five unique variants (13%) in Black/AA participants not previously described in other races (p.Pro81Leu [c.242C>T], p.Leu129Pro [c.386T>C], p.Asp121Val [c.362A>T], p.His110Profs∗49 [c.329del], and p.Arg82His [c.245G>A]). Studies in Japanese, Chinese, and Korean participants have previously reported unique VHL variants in 49%, 28%, and 13% of participants, respectively.7,9,10 Additionally, in Japanese and Chinese populations, previously classified type 1 variants were found in type 2 families.7,9 These findings underscore the importance of studying VHL variants in diverse populations.
Codon 167 variants confer a high risk of pheochromocytoma and RCC.4 Codon 167 variants occur in 7% of Japanese, French, and United Kingdom families, 11% of American families, and more than 5% of Chinese families.4,6,7,9 In comparison, 11% of our Black/AA cohort had codon 167 mutation variants. Due to incomplete history reporting, three participants with the p.Arg167Trp variant were classified as unknown, while one participant with the p.Arg167Gln variant was classified as type 2B, consistent with prior data linking codon 167 variants with pheochromocytoma and RCC.4 Prior studies estimate a 63% risk of developing pheochromocytoma with codon 167 variants.4 Thus, the three participants with unreported histories may also be at high risk for pheochromocytoma, and the true proportion of type 2B disease may be underestimated.
The most common VHL disease type was type 1 (34%), followed by type 2B (11%) and type 2C (5%). No participants were classified as type 2A. It should be noted that 2 participants classified as type 2C had a personal history of pheochromocytoma but had an unknown family history. More complete data might have reclassified them as type 2A or 2B. Nordstrom-O’Brien et al. reported 61% as type 1, 26% as type 2, and 13% as unknown.4 Nearly half of our Black/AA cohort was classified as unknown due to incomplete available history data. Therefore, a definite comparison of the phenotype of our cohort with that of other racial groups is not possible.
RCC was identified in 8% of families in our Black/AA patient cohort compared to 14% in the broader US VHL population.6 In Japan and the United Kingdom, RCC was seen in 12% and 9% of families, respectively.6 Pheochromocytoma was reported in 3% of our cohort’s families versus 35% in the US, 15% in Japan, and 14% in the United Kingdom in VHL families.6 Although RCC and pheochromocytoma appear less frequent among Black/AA families with VHL variants, these comparisons should be interpreted cautiously, as 53% of our cohort had incomplete family history data.
Implications
Until recently, VHL-disease-related tumors were managed with surgery. Belzutifan, a HIF-alpha inhibitor, has since provided a pharmacologic treatment option for patients with VHL-related RCC, hemangioblastoma, or pNETs not requiring immediate surgery.12 Belzutifan was studied in LITESPARK-004, showing an overall response rate of 41% in RCC lesions, 24% in CNS hemangioblastoma, and 20% in pNETs.12 This difference is partly explained by the varying biology of VHL-related tumors.
VHL protein exerts its tumor-suppressor effect by oxygen-dependent ubiquitylation and degradation of HIF-alpha.15 When pVHL is defective or oxygen is low, HIF-alpha escapes degradation, binding to HIF-beta and transcriptionally activating hypoxia response elements. VHL-related tumors differ in their dependence on HIF-alpha, with relative HIF levels being highest in type 1 and lowest in type 2C disease.15 Type 2B pVHL variants lead to higher HIF levels than type 2A, suggesting that hemangioblastoma development requires less HIF activation than RCC and possibly explaining their lower response rate to HIF-alpha inhibition than RCC.12,15 This difference in biology of VHL-related tumors and response to belzutifan warrants further understanding of VHL variant distribution among minority populations. LITESPARK-004 included 90% White and 3% Black/AA participants.12 Our study of Black/AA participants shows 34% as having type 1 disease, suggesting a high likelihood of response to belzutifan. However, this hypothesis warrants further investigation.
Furthermore, 40%–80% of sporadic RCC carry a somatic VHL P/LP variant.16 Belzutifan is approved as a single agent for metastatic RCC after progression on PD1- and VEGF-targeted therapy.17,18 Belzutifan is also being studied in combination with lenvatinib for metastatic RCC and with pembrolizumab for adjuvant therapy of high-risk RCC.16,17 Additional HIF-2alpha inhibitors are also in development, such as AB521, a small-molecule, selective HIF-2alpha inhibitor.19 Representation of Black/AA patients and response evaluation by VHL variant type remain important in these studies.
Limitations
Several limitations warrant consideration. First, demographic and clinical data were dependent on accurate completion of clinician-submitted testing requisition forms, introducing potential reporting bias. Inaccurate or incomplete reporting may explain the high proportion of participants without a reported personal (45%) or family history of cancer (26%), as well as the large percentage with unknown family history (53%). This incomplete reporting informs the high proportion of participants categorized as unknown for the VHL disease class. Notably, approximately 23% of VHL kindreds are reported to have no family history of VHL disease, due in part to de novo pathogenic variants arising in the VHL gene.18 Although 18% of participants in our study were reported to have no family history of VHL disease, over half had unknown family history. It is therefore possible that some participants with unreported family history truly lacked familial VHL disease and that the percentage of de novo variants is larger than observed. However, incomplete clinical documentation precludes definitive conclusions.
A second limitation is our small sample size. Only 38 (8.6%) Black/AA participants were identified out of the 441 who underwent GGT and carried AD VHL P/LP variants. While this may reflect the true proportion of Black/AA patients with VHL disease, such interpretation must be made cautiously, given well-documented disparities in access to genetic services. Studies demonstrate that White patients are more likely to be referred for genetic counseling, receive genetic counseling from licensed professionals, and undergo GGT compared with non-White patients.20 These disparities may contribute to the low number of Black/AA patients tested and raise concern for potential underdiagnosis of VHL disease in this population.
Financial barriers further limit access to GGT. GGT can cost up to $8,000 out of pocket, making testing inaccessible for many individuals.21 Insurance coverage significantly influences access, and prior studies show higher rates of genetic testing among cancer survivors with private insurance.22,23 Socioeconomic disparities may therefore further explain lower testing rates and, consequently, the lower observed proportion of Black/AA participants with VHL disease.
Conclusion
Our study provides patient-level data for a cohort of Black/AA individuals with VHL germline variants. We identified unique variants and highlighted limitations in germline testing in this population. Prospective, multi-center studies are needed to clarify genotype-phenotype correlations and optimize emerging VHL-directed therapies in this historically underrepresented population.
Data and code availability
The published article includes all datasets/code generated or analyzed during this study.
Acknowledgments
The authors would like to thank Invitae for providing patient data, which contributed to the analyses presented in this manuscript. This research received no external funding.
Declaration of interests
The authors declare no competing interests.
Declaration of generative AI and AI-assisted technologies in the writing process
During the preparation of this work, the authors used ChatGPT 5.2 in order to improve readability and language. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.
Contributor Information
Diana Duque, Email: hq2071@wayne.edu.
Elisabeth Heath, Email: heath.elisabeth@mayo.edu.
Web resources
OMIM, https://www.omim.org
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The published article includes all datasets/code generated or analyzed during this study.