{"id":4725,"date":"2025-11-25T11:19:44","date_gmt":"2025-11-25T10:19:44","guid":{"rendered":"https:\/\/blogs.bmj.com\/medical-ethics\/?p=4725"},"modified":"2025-11-25T11:19:44","modified_gmt":"2025-11-25T10:19:44","slug":"variants-of-unknown-significance-in-stem-cell-donation-new-dilemmas-in-genomic-practice","status":"publish","type":"post","link":"https:\/\/blogs.bmj.com\/medical-ethics\/2025\/11\/25\/variants-of-unknown-significance-in-stem-cell-donation-new-dilemmas-in-genomic-practice\/","title":{"rendered":"Variants of unknown significance in stem cell donation \u2013 new dilemmas in genomic practice"},"content":{"rendered":"<p>By <span data-olk-copy-source=\"MessageBody\">Helena Carley, Kate Sahan, Helen Hanson, Katie Snape, Sarah Westbury, Michael J Parker, &amp; Anneke M Lucassen<\/span><\/p>\n<p>Current popular discourse surrounding genomics is frequently one of \u2018clarity\u2019 and \u2018transformation\u2019, concepts projected by <a href=\"https:\/\/assets.publishing.service.gov.uk\/media\/6888a0996478525675738f3a\/fit-for-the-future-10-year-health-plan-for-england-executive-summary.pdf\">the NHS 10 year plan<\/a> and echoed in the media. Technological advances in genomics over recent years have been impressive: whole genome sequencing (WGS) is now routinely offered in the UK for the investigation of rare disease and can be used in acute settings to inform clinical decision-making. Whilst we share the optimism and hope surrounding genomic medicine, genomic practice on the frontline continues to generate new, complex ethical questions about how to act on genomic findings, how we should counsel patients and relatives, and how specialisms should work together when findings are uncertain but action must be taken quickly.<\/p>\n<p>In this paper we show, through a clinical case example of a variant of uncertain significance identified in the context of stem cell donation for leukaemia, how uncertainty can influence clinical decision-making, impact upon interprofessional working and affect the care of patients and their families. We highlight this as one of a number of examples of uncertainty within genomic medicine, arising at various points in the patient pathway:<\/p>\n<ul>\n<li><strong>During variant interpretation<\/strong>: different laboratories may disagree about a variant\u2019s role in disease aetiology which can lead to patients with the same variant receiving different care. As we note in the paper, accumulating evidence can mean that the interpretation of variants change over time impacting on clinical recommendations.<\/li>\n<li><strong>During clinical assessment<\/strong>: population studies show that the likelihood of a given genomic variant exerting an effect is dependent upon the context in which it is detected. Variants once thought to be strongly linked to a particular disease \u2013 because they were found in a disease population \u2013 often predict that disease much more weakly in a general population setting. Now that genomic testing is routinely much broader than the genes linked to a particular disease, it is less clear how such \u2018incidental\u2019 or \u2018off-target\u2019 genomic variants should be managed.<\/li>\n<li><strong>During clinical discussions :<\/strong> even in seemingly straightforward monogenic disorders (where a pathogenic variant might be identified in the context of a consistent clinical history), elements of uncertainty often remain \u2013 for example, the way in which a disease will affect an individual and their relatives, and at what age.<\/li>\n<li><strong>During familial discussions:<\/strong> given scientific and clinical uncertainty, individuals, relatives and practitioners are faced with tough decisions, particularly in our case where the risks of donor derived disease makes a related donor\u2019s cells potentially risky, but even so the donor might feel a familial duty to \u2018do something\u2019 for the patient.<\/li>\n<\/ul>\n<p>In our experience, managing such uncertainty is complex, especially for patients, the general public and health professionals less familiar with genomic medicine. As genomics expands into the prediction of future disease (highlighted through large scale research studies currently investigating <a href=\"https:\/\/www.generationstudy.co.uk\/\">WGS in newborn babies to screen for serious treatable early-onset genetic disorders<\/a> and the use of <a href=\"https:\/\/ourfuturehealth.org.uk\/\">polygenic risk scores to predict common adult-onset disease<\/a>), we need to consider how we can make space to discuss these uncertainties in practice. We think this requires wider discussion than health professional circles, so that patients and the public are included and the promise of genomics and its real life limitations are made clear and expectations become more realistic. To this end, cultivating an <a href=\"https:\/\/jme.bmj.com\/content\/50\/8\/517\">ethically prepared workforce<\/a> plus sustained public engagement is crucial to make sense of, and harness maximum value from, advances in genomic science and medicine.<\/p>\n<div><b data-olk-copy-source=\"MessageBody\">Author(s):\u00a0<\/b>Helena Carley 1, 2, Kate Sahan 3, Helen Hanson 4, 5, Katie Snape 6, 7, Sarah Westbury 8, 9, Michael J Parker 10, Anneke M Lucassen 2<\/div>\n<div><b>Affiliations<\/b>:<\/div>\n<ul>\n<li>\n<div role=\"presentation\">1 <span style=\"font-size: 1rem\">South East Thames Regional Genetics Service, Guy&#8217;s Hospital, London, UK.<\/span><\/div>\n<\/li>\n<li>\n<div role=\"presentation\">2 <span style=\"font-size: 1rem\">University of Oxford Nuffield Department of Medicine, Oxford, UK.<\/span><\/div>\n<\/li>\n<li>\n<div role=\"presentation\">3 <span style=\"font-size: 1rem\">The Ethox Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK\u00a0<\/span><\/div>\n<\/li>\n<li>\n<div role=\"presentation\">4 <span style=\"font-size: 1rem\">Peninsula Regional Genetics Service, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.<\/span><\/div>\n<\/li>\n<li>\n<div role=\"presentation\">5 <span style=\"font-size: 1rem\">Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK.<\/span><\/div>\n<\/li>\n<li>\n<div role=\"presentation\">6 <span style=\"font-size: 1rem\">South West Thames Centre for Genomics, St George&#8217;s University Hospitals NHS Foundation Trust, London, UK.<\/span><\/div>\n<\/li>\n<li>\n<div role=\"presentation\">7 <span style=\"font-size: 1rem\">City St George&#8217;s, University of London, London, UK.<\/span><\/div>\n<\/li>\n<li>\n<div role=\"presentation\">8 <span style=\"font-size: 1rem\">Translational Health Sciences, Bristol Medical School, Bristol, UK.<\/span><\/div>\n<\/li>\n<li>\n<div role=\"presentation\">9 <span style=\"font-size: 1rem\">Department of Haematology, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.<\/span><\/div>\n<\/li>\n<li>\n<div role=\"presentation\">10 <span style=\"font-size: 1rem\">The Ethox Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK<\/span><\/div>\n<\/li>\n<li>11 Oxford Clinical Genetics service, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.<\/li>\n<\/ul>\n<p><strong>Social Media<\/strong>: <a href=\"https:\/\/www.linkedin.com\/company\/ethox-centre\/posts\/?feedView=all\">LinkedIn<\/a><\/p>\n<p><strong>Conflicts of Interest<\/strong>: None to declare<!--TrendMD v2.4.8--><\/p>\n","protected":false},"excerpt":{"rendered":"<p>By Helena Carley, Kate Sahan, Helen Hanson, Katie Snape, Sarah Westbury, Michael J Parker, &amp; Anneke M Lucassen Current popular discourse surrounding genomics is frequently one of \u2018clarity\u2019 and \u2018transformation\u2019, concepts projected by the NHS 10 year plan and echoed in the media. Technological advances in genomics over recent years have been impressive: whole genome [&#8230;]<\/p>\n<p><a class=\"btn btn-secondary understrap-read-more-link\" href=\"https:\/\/blogs.bmj.com\/medical-ethics\/2025\/11\/25\/variants-of-unknown-significance-in-stem-cell-donation-new-dilemmas-in-genomic-practice\/\">Read More&#8230;<\/a><\/p>\n","protected":false},"author":522,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[8048,8124],"tags":[],"class_list":["post-4725","post","type-post","status-publish","format-standard","hentry","category-genetics","category-genomics"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.5 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Variants of unknown significance in stem cell donation \u2013 new dilemmas in genomic practice - Journal of Medical Ethics blog<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/blogs.bmj.com\/medical-ethics\/2025\/11\/25\/variants-of-unknown-significance-in-stem-cell-donation-new-dilemmas-in-genomic-practice\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Variants of unknown significance in stem cell donation \u2013 new dilemmas in genomic practice - Journal of Medical Ethics blog\" \/>\n<meta property=\"og:description\" content=\"By Helena Carley, Kate Sahan, Helen Hanson, Katie Snape, Sarah Westbury, Michael J Parker, &amp; Anneke M Lucassen Current popular discourse surrounding genomics is frequently one of \u2018clarity\u2019 and \u2018transformation\u2019, concepts projected by the NHS 10 year plan and echoed in the media. 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