[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-371807-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-371807-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","uk-clinical-practice-guidelines-for-the-management-of-patients-with-constitutional-pot1-pathogenic-variants","UK clinical practice guidelines for the management of patients with constitutional POT1 pathogenic variants","","Constitutional or germline pathogenic variants in protection of telomeres 1 (POT1) are linked to POT1-tumour predisposition syndrome (POT1-TPDS) and a broad tumour spectrum, including cutaneous melanoma, angiosarcoma, haematological malignancy, and brain tumours. Because POT1 pathogenic variants are rare and surveillance evidence is limited, lifetime cancer risks and the benefit of monitoring for early detection remain uncertain. An expert group reviews the phenotype spectrum and evidence to develop consensus UK best-practice management recommendations.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/uk-clinical-practice-guidelines-for-the-management-of-patients-with-constitutional-pot1-pathogenic-variants/371807/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/uk-clinical-practice-guidelines-for-the-management-of-patients-with-constitutional-pot1-pathogenic-variants/371807.png","ImageObject",300,407,{"name":42,"@type":43},"Jasmine","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-01","2026-09-23",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",10,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What conditions are associated with constitutional POT1 pathogenic variants (POT1-TPDS)?","Question",{"text":63,"@type":64},"POT1-TPDS is associated with tumours including cutaneous melanoma, angiosarcoma, haematological malignancy, and brain tumours.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"Why are lifetime cancer risks for POT1-TPDS still unclear?",{"text":68,"@type":64},"The variants are rare, available data are limited, long-term follow-up is scarce, and current estimates may overestimate risk.",{"name":70,"@type":61,"acceptedAnswer":71},"What do UK clinical practice guidance efforts aim to deliver?",{"text":72,"@type":64},"They synthesize evidence to assess the POT1-TPDS phenotypic spectrum and produce consensus best-practice recommendations for a UK management protocol, given the absence of existing national or international 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variants  \nOlga Tsoulaki, 1,2 D Gareth Evans,2,3 Khushboo Sinha,4 Neil Rajan,5,6 Farah Bakr,4 Helen Hatcher,7 Andrea Napolitano,8,9 Elena Finn, 10 Sunil Iyengar, 11 Aslam Sohaib, 12 Timothy J Sadler, 13 Claire Forde  ,2 Emma Roisin Woodward,2,3 Terri P McVeigh, 14 Marc Tischkowitz, 15 Fiona Lalloo,2 Helen Hanson  16,17  \n► Additional supplemental material is published online only. To view, please visit the journal online ([https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.1136/jmg-2025-110638](10.1136/jmg-2025-110638)) .  \nFor numbered affiliations see end of article.  \nCorrespondence to  \nDr Helen Hanson;  \n[h.hanson@exeter.ac.uk](h.hanson@exeter.ac.uk)  \nReceived 14 January 2025 Accepted 25 March 2025  \n© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.  \nTo cite: Tsoulaki O, Evans DG, Sinha K, et al. J Med Genet Epub ahead of print: [please include Day Month Year] . doi:10 . 1136/ jmg-2025-110638  \nAbsTrACT  \nConstitutional or germline pathogenic variants (GPVs) in protection of telomeres 1 (POT1) are associated with a variety of tumours resulting in the recognition of POT1-tumour predisposition syndrome (POT1-TPDS) . These tumours may include cutaneous melanoma, angiosarcoma, haematological malignancy and brain tumours. Due to the rarity of POT1 GPVs and limited available data, the overall lifetime cancer risks for individuals with POT1-TPDS are unclear. Furthermore, there is scant evidence to support the role of surveillance in early cancer detection in this patient group. A recent international publication suggested a surveillance protocol similar to that used in Li-Fraumeni Syndrome (LFS) could be offered to POT1 pathogenic variant carriers, particularly where there are LFS-like features. However, current evidence for POT1-TPDS is not supportive of an equivalent lifetime cancer risk. Given the inclusion of POT1 in the National Test Directory in England and the need for UK-based guidance, an expert group undertook a literature review to assess the phenotypic spectrum of POT1-TPDS and to provide lifetime risk estimates of POT1-associated cancers. The available evidence was shared with a small working group of experts that included clinical geneticists, dermatologists, sarcoma specialists, haematologistsand radiologists to cover all aspects of the cancers most commonly associated with POT1-TPDS. Following structured expert group discussions, we achieved consensus on best practice recommendations for a POT1-TPDS UK management protocol.  \nbACkground  \nA growing body of epidemiological evidence has shown that excessively long telomeres are associated with increased cancer predisposition. This finding led to the identification of genomic rare variants in telomeric shelterin components (reviewed in a study by Kim et al1). Protection of telomeres 1 (POT1) is a component of the shelterin complex that has a critical role in regulating telomere length.1 2 Germline pathogenic variants (GPVs), including likely pathogenic (LP) variants, in POT1 have been associated with a variety of tumours resulting in the recognition of POT1-tumour predisposition syndrome (POT1-TPDS). Two independent studies reported an association of GPVs in POT1 with familial melanoma.3 4 Further core ‘POT1 associated tumours’ including angiosarcoma (AS), haematological malignancy and brain  \ntumours have been suggested.5–7 A wide phenotypic spectrum of cancer types, including other sarcomas, colorectal and thyroid cancer, has been described within POT1-TPDS families.8 9  \nPOT1-TPDS is inherited in an autosomal dominant manner. Identifying GPVs in POT1 may help explain a personal or family history of cancer, help tailor early cancer detection and prevention strategies in individuals with a POT1 GPV and facilitate predictive (also known as pre-symptomatic or familial) testing and onward managem","cbCaiqs1FTmIfE5P","https://ap.wps.com/l/cbCaiqs1FTmIfE5P","pdf",272048,"English","# AbsTrACT\n# bACkground\n## Inheritance and clinical rationale\n## Evidence gaps and lifetime risk uncertainty\n## Need for UK guidance and consensus recommendations","[{\"question\":\"What conditions are associated with constitutional POT1 pathogenic variants (POT1-TPDS)?\",\"answer\":\"POT1-TPDS is associated with tumours including cutaneous melanoma, angiosarcoma, haematological malignancy, and brain tumours.\"},{\"question\":\"Why are lifetime cancer risks for POT1-TPDS still unclear?\",\"answer\":\"The variants are rare, available data are limited, long-term follow-up is scarce, and current estimates may overestimate risk.\"},{\"question\":\"What do UK clinical practice guidance efforts aim to deliver?\",\"answer\":\"They synthesize evidence to assess the POT1-TPDS phenotypic spectrum and produce consensus best-practice recommendations for a UK management protocol, given the absence of existing national or international guidelines.\"}]","UK clinical practice guidelines for the management of patients with constitutional POT1 pathogenic variants | PDF",1790192912,18]