Splenic hamartoma in two related patients with BAP1 tumour predisposition syndrome caused by a novel germline BAP1 p.(Gly128Arg) missense variant

Splenic hamartoma in two related patients with BAP1 tumour predisposition syndrome caused by a novel germline BAP1 p.(Gly128Arg) missense variant | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Splenic hamartoma in two related patients with BAP1 tumour predisposition syndrome caused by a novel germline BAP1 p.(Gly128Arg) missense variant Kristjan Ari Ragnarsson, Gloria Garcia, Jon Gunnlaugur Jonasson, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7942438/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Feb, 2026 Read the published version in Familial Cancer → Version 1 posted 9 You are reading this latest preprint version Abstract BAP1 tumour predisposition syndrome ( BAP1 -TPDS) is a hereditary cancer syndrome caused by heterozygous pathogenic germline variants in BAP1 . BAP1 -TPDS is associated with an increased risk for various malignant tumours, the core of which is uveal and cutaneous melanoma, malignant mesothelioma, and renal cell carcinoma. In BAP1 -TPDS, the majority of disease-causing BAP1 variants are null variants, although missense variants have been reported. We report a patient with BAP1 -TPDS caused by the novel germline BAP1 missense variant NM_004656.4:c.382G > A, p.(Gly128Arg). The patient developed BAP1 -inactivated melanocytic tumours, renal cell carcinoma, and splenic hamartoma, all of which showed nuclear loss of BAP1 expression on immunohistochemistry. An incidental splenic hamartoma was detected in existing tissue slides from the patient’s first-degree relative, who was an obligate carrier for BAP1 -TPDS. To our knowledge, this is the first report of a confirmed BAP1 -deficient splenic hamartoma in a patient with BAP1 -TPDS. It supports expanding the tumour spectrum of BAP1 -TPDS to splenic hamartoma and possibly other benign splenic tumours. BAP1 tumour predisposition syndrome Splenic hamartoma BAP1 missense variant BAP1 immunohistochemistry Figures Figure 1 Figure 2 Figure 3 1. Introduction The BRCA1-associated protein 1 gene ( BAP1 ; OMIM *603089 ) is a tumour suppressor gene that encodes a deubiquitinase involved in DNA repair and epigenetic regulation [ 1 , 2 ]. Heterozygous loss-of-function pathogenic germline BAP1 variants are associated with autosomal dominant BAP1 tumour predisposition syndrome ( BAP1 -TPDS; OMIM #614327 ). Core tumours of BAP1-TPDS include uveal and cutaneous melanoma, pleural and peritoneal mesothelioma, renal cell carcinoma (RCC; predominantly clear cell), and benign BAP1 -inactivated melanocytic tumours (BIMTs). BIMTs rarely transform to melanoma. Other tumours include meningioma, basal cell carcinoma, and cholangiocarcinoma [ 3 , 4 ]. In a case series, Miranda et al. (2024) provided the first indication of an association between BAP1 -TPDS and benign splenic lesions, including a suspected splenic hamartoma [ 5 ]. The mechanism of tumour formation in BAP1 -TPDS involves a somatic variant in the second BAP1 allele or loss of heterozygosity, leading to biallelic BAP1 loss. Immunohistochemistry (IHC) on BAP1 -deficient tumours shows absent nuclear staining for BAP1, reflecting loss of nuclear BAP1 expression [ 3 ]. Lifetime risks are estimated to be 20–25% for uveal/cutaneous melanoma and mesothelioma, and lower for other tumours. Overall lifetime risk for at least one tumour is as high as 85%. The risk estimates may be inflated due to ascertainment bias [ 3 , 6 ]. The increased risk for malignant pleural mesothelioma may partly be mediated by increased asbestos sensitivity [ 7 ]. We describe a patient with a previously unreported germline BAP1 missense variant who developed BIMTs, clear cell RCC, and splenic hamartoma. The tumours all showed loss of nuclear BAP1 staining on IHC. This report provides evidence for the addition of splenic hamartoma to the tumour spectrum of BAP1 -TPDS. 2. Subject, materials, and methods Case presentation The proband (hereafter ‘the patient’) is a female with a complex tumour history. She was diagnosed with uterine leiomyoma at age 34, followed by splenic hamartoma and clear cell RCC at age 35. The patient developed multiple skin lesions throughout her life. Additional diagnoses included primary hyperaldosteronism caused by bilateral adrenal hyperplasia, and reactive thrombocytosis (negative JAK2 , CALR , and MPL somatic mutations). Family history Family history revealed two deceased relatives with BAP1 -TPDS-associated tumours: (1) First-degree relative : atypical meningioma at 44 years; aggressive clinical course with two postoperative recurrences, resulting in terminal disease. Additional medical history of splenectomy for splenomegaly at 36 years; splenic histology showed extramedullary haematopoiesis with myeloid-lineage expansion. (2) Second-degree relative : RCC at age 62 (histological subtype unknown). Detailed pedigree and family history not included due to privacy reasons. BAP1 IHC IHC with BAP-1 (BRCA1-Associated Protein 1) antibody, clone C-4, from Santa Cruz Biotechnology (Texas, USA) was performed on FFPE tissue slides from the patient’s RCC, splenic hamartoma, uterine leiomyoma, and three skin lesions, and the first-degree relative’s spleen. Genetic testing Genomic DNA was extracted from peripheral blood using the QIAamp DNA Mini Kit (QIAGEN). The extracted DNA was sent to Fulgent Genetics (California, USA) for Comprehensive Cancer Panel analysis. A buccal swab was also sent to deCODE Genetics (Reykjavik, Iceland) for whole-genome sequencing. Variant classification based on the ACMG/AMP guidelines for classification of sequence variants was performed locally [ 8 ]. The online variant evaluation tool Franklin by Genoox was used [ 9 ]. AlphaMissense (Google DeepMind) was among the in silico tools applied to predict missense-variant pathogenicity [ 10 ]. 3. Results BAP1 IHC results The results of BAP1 IHC are shown in table 1. Table 1. BAP1 immunohistochemistry results Sample BAP1 nuclear staining Note Skin lesions (patient) Absent Histopathological features were consistent with BIMTs. Diagnosed as BIMTs. Renal cell carcinoma (patient) Absent BAP1 -TPDS core tumour. Splenic hamartoma (patient) Absent See Discussion. Uterine leiomyoma (patient) Present Not a BAP1 -TPDS-associated tumour. Presumably sporadic. Splenic hamartoma (1° relative) Absent Re-evaluation of the splenic sample revealed an incidental splenic hamartoma with absent BAP1 nuclear staining (see Discussion). Abbreviations : IHC, immunohistochemistry; BIMTs, BAP1 -inactivated melanocytic tumours; BAP1 -TPDS, BAP1 tumour predisposition syndrome. Genetic testing results Genetic testing identified a heterozygous BAP1 variant, NM_004656.4:c.382G>A, p.(Gly128Arg). The variant is absent from gnomAD v4.1.0. Among approximately 70,000 whole-genome sequenced Icelanders at deCODE genetics, there are only two carriers of the variant, the patient and a close relative. Their common ancestor was born in the 1920s, indicating that the variant is private to the family. Segregation analysis showed that the affected relatives were obligate carriers. The authors classified the variant as pathogenic (ACMG/AMP criteria PS3, PM1, PM2_supporting, PP1, PP3, and PP4; see Supplementary Material). The variant was submitted to ClinVar (submission ID: SUB15454254). BAP1 -TPDS surveillance was initiated and cascade testing was offered to at-risk relatives. 4. Discussion The p.Gly128Arg variant in BAP1 has been reported as a somatic variant in uveal melanoma and peritoneal mesothelioma [11–13]. Our finding demonstrates that in addition to this, it is a disease-causing germline variant that leads to BAP1 -TPDS. Our segregation of the variant within the patient‘s family has confirmed its germline status. Additionally, our finding adds to recent evidence of splenic hamartomas being a BAP1 -TPDS-associated tumour [5]. The ubiquitin carboxy-terminal hydrolase (UCH) domain of the BAP1 protein The p.Gly128Arg variant is located in the UCH domain (amino acids 1–240) of the BAP1 protein. The UCH domain is responsible for BAP1’s deubiquitinating activity. Glycine, a hydrophobic residue, is replaced by arginine, a large polar charged residue. This would be expected to disrupt the integrity of the UCH domain presumably leading to loss of its function [14]. Waters et al. (2024) used saturation genome editing in a BAP1 -dependent haploid cell model to functionally characterize 18,108 unique BAP1 variants. Deleterious variants reduced cell fitness and were classified as functionally depleted. The p.Gly128Arg variant was classified as functionally depleted [15]. Walpole et al. (2018) identified 36 unique germline BAP1 missense variants in a review of BAP1 variant-carrying families. The authors classified nine of the 36 missense variants as likely pathogenic. All nine variants were in the UCH domain of BAP1, consistent with it being a critical domain [3]. Splenic hamartoma in BAP1 -TPDS Our finding of loss of BAP1 expression on IHC in the splenic hamartomas of the patient and the patient’s first-degree relative supports expanding the tumour spectrum of BAP1 -TPDS. Consistent with this, benign splenic lesions, including a suspected splenic hamartoma based on imaging, were reported as possible BAP1 -TPDS-associated tumours in a small case series [5]. BAP1 and haematopoiesis Postnatal Bap1 knockout in mice causes myelodysplasia, myeloid skewing, ineffective haematopoiesis, and splenomegaly caused by extramedullary haematopoiesis and myeloid lineage expansion [16]. Dual Bap1 / Ezh2 knockout does not cause the phenotype, indicating the myeloid expansion is Ezh2-dependent [17]. This data suggests that there is a link between the obligate-carrier relative‘s splenomegaly (caused by extramedullary haematopoiesis and myeloid lineage expansion) and BAP1 -TPDS. While hypothesis-generating, this preliminary observation of a single case requires further corroboration in additional patients with BAP1 -TPDS. BAP1 -altered meningioma Meningioma is among the less common BAP1 -TPDS-associated tumours [3]. Somatic BAP1 variants are known to occur in meningioma. BAP1 -altered meningiomas represent <1% of all meningiomas, but a small case series showed that 50% arose in the setting of BAP1 -TPDS [18]. BAP1 -altered meningioma has been suggested to represent a distinct and aggressive CNS tumour subtype [19]. Although BAP1 IHC was not performed on the meningioma of the patient’s obligate-carrier relative, its aggressive clinical course is consistent with what has been reported on BAP1 -altered meningioma. Conclusion We report the first confirmed BAP1 -deficient splenic hamartomas in two patients with BAP1 -TPDS. This case report adds NM_004656.4( BAP1 ):c.382G>A, p.(Gly128Arg) to the list of reported germline BAP1 missense variants that cause BAP1 -TPDS and provides evidence that splenic hamartoma can be part of the BAP1 -TPDS tumour spectrum. Furthermore, it demonstrates the utility of BAP1 IHC in the evaluation of germline BAP1 variants. The patient’s bilateral adrenal hyperplasia and reactive thrombocytosis were presumably coincidental, as there are currently no known associations between these clinical features and BAP1 -TPDS. Declarations Consent to Publish The participant has consented to the submission of the case report to the journal. Data Availability Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Acknowledgements The authors thank the patient for participation. Author Contributions Contributed to the clinical characterization of the patient and the family: GAA, GG, JGJ, RA, SER, SH Histopathological special studies: JGJ Conceptualization and supervision: JJJ Wrote the draft: KAR, JJJ All authors reviewed the draft. Funding Departmental funding. No other sources of funding. Ethical Approval Ethical approval not required for this case study according to the national bioethics committee of Iceland. Competing Interests The authors declare no conflict of interest. References Daou S, Hammond-Martel I, Mashtalir N, Barbour H, Gagnon J, Iannantuono NVG, et al. 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Epub 2025 Apr 18. https://doi.org/10.1093/neuonc/noaf105 Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.docx Cite Share Download PDF Status: Published Journal Publication published 19 Feb, 2026 Read the published version in Familial Cancer → Version 1 posted Editorial decision: Revision requested 10 Nov, 2025 Reviews received at journal 10 Nov, 2025 Reviews received at journal 29 Oct, 2025 Reviewers agreed at journal 29 Oct, 2025 Reviewers agreed at journal 29 Oct, 2025 Reviewers invited by journal 29 Oct, 2025 Editor assigned by journal 28 Oct, 2025 Submission checks completed at journal 28 Oct, 2025 First submitted to journal 24 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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07:13:48","extension":"html","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":71283,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7942438/v1/a1cad3168e65ba9c8e02426b.html"},{"id":95510299,"identity":"a35e263a-0b63-4358-bf66-cf2bd465997d","added_by":"auto","created_at":"2025-11-10 07:13:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":576188,"visible":true,"origin":"","legend":"\u003cp\u003eBAP1 IHC of spleen (low-power view), patient. The dotted line marks the approximate boundary between normal splenic tissue (left) and the hamartoma (right)\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7942438/v1/d7f972adbd2b57e0eb988df6.png"},{"id":95529546,"identity":"1f424917-590c-42b2-a58a-d339c3608133","added_by":"auto","created_at":"2025-11-10 10:17:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":641170,"visible":true,"origin":"","legend":"\u003cp\u003eBAP1 IHC of splenic hamartoma (high-power view), patient. Upper arrow: hamartoma cell with absent BAP1 nuclear staining. Lower arrow: non-hamartomatous cell with preserved BAP1 nuclear staining. Note: Brown nuclear coloration indicates preserved BAP1 nuclear staining; absence of nuclear staining indicates BAP1 loss\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7942438/v1/7d79bbff5468cc98a2078db2.png"},{"id":95510300,"identity":"ae37eb06-3321-4dd4-9f2a-de1383d88a91","added_by":"auto","created_at":"2025-11-10 07:13:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":557094,"visible":true,"origin":"","legend":"\u003cp\u003eBAP1 IHC of spleen (high-power view), first-degree relative. Arrow: hamartoma cell with absent BAP1 nuclear staining. Note: brown nuclear coloration indicates preserved BAP1 nuclear staining; absence of nuclear staining indicates BAP1 loss\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7942438/v1/acdfdd9b68890c56dc4eb361.png"},{"id":103251361,"identity":"5e4b18f7-8958-4faf-a1bb-0c8734064e4e","added_by":"auto","created_at":"2026-02-23 16:08:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2573691,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7942438/v1/d65a4905-a9de-46a1-b04e-66f44f28c086.pdf"},{"id":95510302,"identity":"b54bbe36-e8e4-4ffd-a0ef-8f8d40059f1e","added_by":"auto","created_at":"2025-11-10 07:13:47","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":749582,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-7942438/v1/086da2425431d80a803cbd5c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Splenic hamartoma in two related patients with BAP1 tumour predisposition syndrome caused by a novel germline BAP1 p.(Gly128Arg) missense variant","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eThe BRCA1-associated protein 1 gene (\u003cem\u003eBAP1\u003c/em\u003e; OMIM \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e*603089\u003c/span\u003e) is a tumour suppressor gene that encodes a deubiquitinase involved in DNA repair and epigenetic regulation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Heterozygous loss-of-function pathogenic germline \u003cem\u003eBAP1\u003c/em\u003e variants are associated with autosomal dominant \u003cem\u003eBAP1\u003c/em\u003e tumour predisposition syndrome (\u003cem\u003eBAP1\u003c/em\u003e-TPDS; OMIM \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e#614327\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eCore tumours of BAP1-TPDS include uveal and cutaneous melanoma, pleural and peritoneal mesothelioma, renal cell carcinoma (RCC; predominantly clear cell), and benign \u003cem\u003eBAP1\u003c/em\u003e-inactivated melanocytic tumours (BIMTs). BIMTs rarely transform to melanoma. Other tumours include meningioma, basal cell carcinoma, and cholangiocarcinoma [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In a case series, Miranda et al. (2024) provided the first indication of an association between \u003cem\u003eBAP1\u003c/em\u003e-TPDS and benign splenic lesions, including a suspected splenic hamartoma [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe mechanism of tumour formation in \u003cem\u003eBAP1\u003c/em\u003e-TPDS involves a somatic variant in the second \u003cem\u003eBAP1\u003c/em\u003e allele or loss of heterozygosity, leading to biallelic \u003cem\u003eBAP1\u003c/em\u003e loss. Immunohistochemistry (IHC) on \u003cem\u003eBAP1\u003c/em\u003e-deficient tumours shows absent nuclear staining for BAP1, reflecting loss of nuclear BAP1 expression [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eLifetime risks are estimated to be 20\u0026ndash;25% for uveal/cutaneous melanoma and mesothelioma, and lower for other tumours. Overall lifetime risk for at least one tumour is as high as 85%. The risk estimates may be inflated due to ascertainment bias [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The increased risk for malignant pleural mesothelioma may partly be mediated by increased asbestos sensitivity [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe describe a patient with a previously unreported germline \u003cem\u003eBAP1\u003c/em\u003e missense variant who developed BIMTs, clear cell RCC, and splenic hamartoma. The tumours all showed loss of nuclear BAP1 staining on IHC. This report provides evidence for the addition of splenic hamartoma to the tumour spectrum of \u003cem\u003eBAP1\u003c/em\u003e-TPDS.\u003c/p\u003e"},{"header":"2. Subject, materials, and methods","content":"\u003cp\u003e\u003cb\u003eCase presentation\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe proband (hereafter \u0026lsquo;the patient\u0026rsquo;) is a female with a complex tumour history. She was diagnosed with uterine leiomyoma at age 34, followed by splenic hamartoma and clear cell RCC at age 35. The patient developed multiple skin lesions throughout her life. Additional diagnoses included primary hyperaldosteronism caused by bilateral adrenal hyperplasia, and reactive thrombocytosis (negative \u003cem\u003eJAK2\u003c/em\u003e, \u003cem\u003eCALR\u003c/em\u003e, and \u003cem\u003eMPL\u003c/em\u003e somatic mutations).\u003c/p\u003e\u003cp\u003e\u003cb\u003eFamily history\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFamily history revealed two deceased relatives with \u003cem\u003eBAP1\u003c/em\u003e-TPDS-associated tumours:\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e(1) \u003cb\u003eFirst-degree relative\u003c/b\u003e: atypical meningioma at 44 years; aggressive clinical course with two postoperative recurrences, resulting in terminal disease. Additional medical history of splenectomy for splenomegaly at 36 years; splenic histology showed extramedullary haematopoiesis with myeloid-lineage expansion.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e(2) \u003cb\u003eSecond-degree relative\u003c/b\u003e: RCC at age 62 (histological subtype unknown).\u003c/p\u003e\u003cp\u003eDetailed pedigree and family history not included due to privacy reasons.\u003c/p\u003e\u003cp\u003e\u003cb\u003eBAP1 IHC\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIHC with BAP-1 (BRCA1-Associated Protein 1) antibody, clone C-4, from Santa Cruz Biotechnology (Texas, USA) was performed on FFPE tissue slides from the patient\u0026rsquo;s RCC, splenic hamartoma, uterine leiomyoma, and three skin lesions, and the first-degree relative\u0026rsquo;s spleen.\u003c/p\u003e\u003cp\u003e\u003cb\u003eGenetic testing\u003c/b\u003e\u003c/p\u003e\u003cp\u003eGenomic DNA was extracted from peripheral blood using the QIAamp DNA Mini Kit (QIAGEN). The extracted DNA was sent to Fulgent Genetics (California, USA) for Comprehensive Cancer Panel analysis. A buccal swab was also sent to deCODE Genetics (Reykjavik, Iceland) for whole-genome sequencing. Variant classification based on the ACMG/AMP guidelines for classification of sequence variants was performed locally [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The online variant evaluation tool Franklin by Genoox was used [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. AlphaMissense (Google DeepMind) was among the \u003cem\u003ein silico\u003c/em\u003e tools applied to predict missense-variant pathogenicity [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003eBAP1 IHC results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of BAP1 IHC are shown in table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eBAP1 immunohistochemistry results\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBAP1 nuclear staining\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNote\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eSkin lesions (patient)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eHistopathological features were consistent with BIMTs. Diagnosed as BIMTs.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eRenal cell carcinoma (patient)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u003cem\u003eBAP1\u003c/em\u003e-TPDS core tumour.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eSplenic hamartoma (patient)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eSee Discussion.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eUterine leiomyoma (patient)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eNot a \u003cem\u003eBAP1\u003c/em\u003e-TPDS-associated tumour. Presumably sporadic.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eSplenic hamartoma (1\u0026deg; relative)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eRe-evaluation of the splenic sample revealed an incidental splenic hamartoma with absent BAP1 nuclear staining (see Discussion).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations\u003c/em\u003e: IHC, immunohistochemistry; BIMTs, \u003cem\u003eBAP1\u003c/em\u003e-inactivated melanocytic tumours; \u003cem\u003eBAP1\u003c/em\u003e-TPDS, \u003cem\u003eBAP1\u0026nbsp;\u003c/em\u003etumour predisposition syndrome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenetic testing results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGenetic testing identified a heterozygous \u003cem\u003eBAP1\u003c/em\u003e variant, NM_004656.4:c.382G\u0026gt;A, p.(Gly128Arg). The variant is absent from gnomAD v4.1.0. Among approximately 70,000 whole-genome sequenced Icelanders at deCODE genetics, there are only two carriers of the variant, the patient and a close relative. Their common ancestor was born in the 1920s, indicating that the variant is private to the family. Segregation analysis showed that the affected relatives were obligate carriers. The authors classified the variant as pathogenic (ACMG/AMP criteria PS3, PM1, PM2_supporting, PP1, PP3, and PP4; see Supplementary Material). The variant was submitted to ClinVar (submission ID: SUB15454254). \u003cem\u003eBAP1\u003c/em\u003e-TPDS surveillance was initiated and cascade testing was offered to at-risk relatives.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe p.Gly128Arg variant in \u003cem\u003eBAP1\u003c/em\u003e has been reported as a somatic variant in uveal melanoma and peritoneal mesothelioma [11–13]. Our finding demonstrates that in addition to this, it is a disease-causing germline variant that leads to \u003cem\u003eBAP1\u003c/em\u003e-TPDS. Our segregation of the variant within the patient‘s family has confirmed its germline status. Additionally, our finding adds to recent evidence of splenic hamartomas being a \u003cem\u003eBAP1\u003c/em\u003e-TPDS-associated tumour [5].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe ubiquitin carboxy-terminal hydrolase (UCH) domain of the BAP1 protein\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe p.Gly128Arg variant is located in the UCH domain (amino acids 1–240) of the BAP1 protein. The UCH domain is responsible for BAP1’s deubiquitinating activity. Glycine, a hydrophobic residue, is replaced by arginine, a large polar charged residue. This would be expected to disrupt the integrity of the UCH domain presumably leading to loss of its function [14]. Waters et al. (2024) used saturation genome editing in a \u003cem\u003eBAP1\u003c/em\u003e-dependent haploid cell model to functionally characterize 18,108 unique \u003cem\u003eBAP1\u003c/em\u003e variants. Deleterious variants reduced cell fitness and were classified as functionally depleted. The p.Gly128Arg variant was classified as functionally depleted [15]. Walpole et al. (2018) identified 36 unique germline \u003cem\u003eBAP1\u003c/em\u003e missense variants in a review of \u003cem\u003eBAP1\u003c/em\u003e variant-carrying families. The authors classified nine of the 36 missense variants as likely pathogenic. All nine variants were in the UCH domain of BAP1, consistent with it being a critical domain [3].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSplenic hamartoma in \u003cem\u003eBAP1\u003c/em\u003e-TPDS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur finding of loss of BAP1 expression on IHC in the splenic hamartomas of the patient and the patient’s first-degree relative supports expanding the tumour spectrum of \u003cem\u003eBAP1\u003c/em\u003e-TPDS. Consistent with this, benign splenic lesions, including a suspected splenic hamartoma based on imaging, were reported as possible \u003cem\u003eBAP1\u003c/em\u003e-TPDS-associated tumours in a small case series [5].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBAP1\u003c/em\u003e and haematopoiesis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePostnatal \u003cem\u003eBap1\u003c/em\u003e knockout in mice causes myelodysplasia, myeloid skewing, ineffective haematopoiesis, and splenomegaly caused by extramedullary haematopoiesis and myeloid lineage expansion [16]. Dual \u003cem\u003eBap1\u003c/em\u003e/\u003cem\u003eEzh2\u003c/em\u003e knockout does not cause the phenotype, indicating the myeloid expansion is Ezh2-dependent [17].\u003c/p\u003e\n\u003cp\u003eThis data suggests that there is a link between the obligate-carrier relative‘s splenomegaly (caused by extramedullary haematopoiesis and myeloid lineage expansion) and \u003cem\u003eBAP1\u003c/em\u003e-TPDS. While hypothesis-generating, this preliminary observation of a single case requires further corroboration in additional patients with \u003cem\u003eBAP1\u003c/em\u003e-TPDS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBAP1\u003c/em\u003e-altered meningioma\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMeningioma is among the less common \u003cem\u003eBAP1\u003c/em\u003e-TPDS-associated tumours [3]. Somatic \u003cem\u003eBAP1\u003c/em\u003e variants are known to occur in meningioma. \u003cem\u003eBAP1\u003c/em\u003e-altered meningiomas represent \u0026lt;1% of all meningiomas, but a small case series showed that 50% arose in the setting of \u003cem\u003eBAP1\u003c/em\u003e-TPDS [18]. \u003cem\u003eBAP1\u003c/em\u003e-altered meningioma has been suggested to represent a distinct and aggressive CNS tumour subtype [19]. Although BAP1 IHC was not performed on the meningioma of the patient’s obligate-carrier relative, its aggressive clinical course is consistent with what has been reported on \u003cem\u003eBAP1\u003c/em\u003e-altered meningioma.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe report the first confirmed \u003cem\u003eBAP1\u003c/em\u003e-deficient splenic hamartomas in two patients with \u003cem\u003eBAP1\u003c/em\u003e-TPDS. This case report adds NM_004656.4(\u003cem\u003eBAP1\u003c/em\u003e):c.382G\u0026gt;A, p.(Gly128Arg) \u0026nbsp;to the list of reported germline \u003cem\u003eBAP1\u003c/em\u003e missense variants that cause \u003cem\u003eBAP1\u003c/em\u003e-TPDS and provides evidence that splenic hamartoma can be part of the \u003cem\u003eBAP1\u003c/em\u003e-TPDS tumour spectrum. Furthermore, it demonstrates the utility of BAP1 IHC in the evaluation of germline \u003cem\u003eBAP1\u003c/em\u003e variants. The patient’s bilateral adrenal hyperplasia and reactive thrombocytosis were presumably coincidental, as there are currently no known associations between these clinical features and \u003cem\u003eBAP1\u003c/em\u003e-TPDS.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eConsent to Publish\u003c/p\u003e\n\u003cp\u003eThe participant has consented to the submission of the case report to the journal.\u003c/p\u003e\n\u003cp\u003eData Availability Statement\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors thank the patient for participation.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eContributed to the clinical characterization of the patient and the family: \u003cstrong\u003eGAA, GG, JGJ, RA, SER, SH\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHistopathological special studies: \u003cstrong\u003eJGJ\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization and supervision: \u003cstrong\u003eJJJ\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWrote the draft:\u003cstrong\u003e\u0026nbsp;KAR, JJJ\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors reviewed the draft.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eDepartmental funding. No other sources of funding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEthical Approval\u003c/p\u003e\n\u003cp\u003eEthical approval not required for this case study according to the national bioethics committee of Iceland.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting Interests\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDaou S, Hammond-Martel I, Mashtalir N, Barbour H, Gagnon J, Iannantuono NVG, et al. The BAP1/ASXL2 histone H2A deubiquitinase complex regulates cell proliferation and is disrupted in cancer. J Biol Chem. 2015 Nov 27;290(48):28643\u0026ndash;63. https://doi.org/10.1074/jbc.M115.661553 \u003c/li\u003e\n\u003cli\u003eYu H, Pak H, Hammond-Martel I, Ghram M, Rodrigue A, Daou S, et al. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. 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Available from: https://tumourclassification.iarc.who.int/chapters/45. \u003c/li\u003e\n\u003cli\u003eSievers P, Arora S, Hielscher T, Savran D, Schrimpf D, Banan R, et al. Molecular signatures define BAP1-altered meningioma as a distinct CNS tumor with deregulation of Polycomb repressive complex target genes. Neuro Oncol. 2025 Apr 18:noaf105. doi:10.1093/neuonc/noaf105. Epub 2025 Apr 18. https://doi.org/10.1093/neuonc/noaf105 \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"familial-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"fame","sideBox":"Learn more about [Familial Cancer](http://link.springer.com/journal/10689)","snPcode":"10689","submissionUrl":"https://submission.nature.com/new-submission/10689/3","title":"Familial Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"BAP1 tumour predisposition syndrome, Splenic hamartoma, BAP1 missense variant, BAP1 immunohistochemistry","lastPublishedDoi":"10.21203/rs.3.rs-7942438/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7942438/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eBAP1\u003c/em\u003e tumour predisposition syndrome (\u003cem\u003eBAP1\u003c/em\u003e-TPDS) is a hereditary cancer syndrome caused by heterozygous pathogenic germline variants in \u003cem\u003eBAP1\u003c/em\u003e. \u003cem\u003eBAP1\u003c/em\u003e-TPDS is associated with an increased risk for various malignant tumours, the core of which is uveal and cutaneous melanoma, malignant mesothelioma, and renal cell carcinoma. In \u003cem\u003eBAP1\u003c/em\u003e-TPDS, the majority of disease-causing \u003cem\u003eBAP1\u003c/em\u003e variants are null variants, although missense variants have been reported. We report a patient with \u003cem\u003eBAP1\u003c/em\u003e-TPDS caused by the novel germline \u003cem\u003eBAP1\u003c/em\u003e missense variant NM_004656.4:c.382G\u0026thinsp;\u0026gt;\u0026thinsp;A, p.(Gly128Arg). The patient developed \u003cem\u003eBAP1\u003c/em\u003e-inactivated melanocytic tumours, renal cell carcinoma, and splenic hamartoma, all of which showed nuclear loss of BAP1 expression on immunohistochemistry. An incidental splenic hamartoma was detected in existing tissue slides from the patient\u0026rsquo;s first-degree relative, who was an obligate carrier for \u003cem\u003eBAP1\u003c/em\u003e-TPDS. To our knowledge, this is the first report of a confirmed \u003cem\u003eBAP1\u003c/em\u003e-deficient splenic hamartoma in a patient with \u003cem\u003eBAP1\u003c/em\u003e-TPDS. It supports expanding the tumour spectrum of \u003cem\u003eBAP1\u003c/em\u003e-TPDS to splenic hamartoma and possibly other benign splenic tumours.\u003c/p\u003e","manuscriptTitle":"Splenic hamartoma in two related patients with BAP1 tumour predisposition syndrome caused by a novel germline BAP1 p.(Gly128Arg) missense variant","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-10 07:13:43","doi":"10.21203/rs.3.rs-7942438/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-10T14:39:23+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-10T14:31:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-29T21:17:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"173499152709941164074657211936175424506","date":"2025-10-29T17:56:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"128961904299309092615420807304019753435","date":"2025-10-29T12:05:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-29T07:59:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-28T04:37:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-28T04:36:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"Familial Cancer","date":"2025-10-24T17:01:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"familial-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"fame","sideBox":"Learn more about [Familial Cancer](http://link.springer.com/journal/10689)","snPcode":"10689","submissionUrl":"https://submission.nature.com/new-submission/10689/3","title":"Familial Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"feb51b53-5ef4-4cbc-91a6-c7e804719618","owner":[],"postedDate":"November 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-23T16:05:20+00:00","versionOfRecord":{"articleIdentity":"rs-7942438","link":"https://doi.org/10.1007/s10689-026-00538-3","journal":{"identity":"familial-cancer","isVorOnly":false,"title":"Familial Cancer"},"publishedOn":"2026-02-19 15:58:39","publishedOnDateReadable":"February 19th, 2026"},"versionCreatedAt":"2025-11-10 07:13:43","video":"","vorDoi":"10.1007/s10689-026-00538-3","vorDoiUrl":"https://doi.org/10.1007/s10689-026-00538-3","workflowStages":[]},"version":"v1","identity":"rs-7942438","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7942438","identity":"rs-7942438","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}