{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T18:06:42Z","timestamp":1788977202360,"version":"build-2803163510"},"reference-count":29,"publisher":"BMJ","funder":[{"DOI":"10.13039\/100010733","name":"Danish Childhood Cancer Foundation","doi-asserted-by":"crossref","award":["2019-5949"],"award-info":[{"award-number":["2019-5949"]}],"id":[{"id":"10.13039\/100010733","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2026,8,26]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Classification of heterozygous germline\n                      <jats:italic>PTEN<\/jats:italic>\n                      variants in patients with, or suspected of having,\n                      <jats:italic>PTEN<\/jats:italic>\n                      hamartoma tumour syndrome (PHTS) remains challenging. Accurate classification is essential as these patients require lifelong cancer surveillance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We identified all patients with a\n                      <jats:italic>PTEN<\/jats:italic>\n                      variant previously classified as a variant of uncertain significance (VUS), likely pathogenic (LP) or pathogenic (P), collected clinical data and reclassified all variants using the latest\n                      <jats:italic>PTEN<\/jats:italic>\n                      gene-specific American College of Medical Genetics (ACMG) guidelines. Moreover, genotype-phenotype correlations were assessed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      167 patients from 112 families were enrolled. Eighty-seven unique\n                      <jats:italic>PTEN<\/jats:italic>\n                      variants were identified, including 20 novel variants. After applying the\n                      <jats:italic>PTEN<\/jats:italic>\n                      gene\n                      <jats:italic>-<\/jats:italic>\n                      specific ACMG guidelines, 32 variants (36.8%) were reclassified, resulting in 60\n                      <jats:italic>PTEN<\/jats:italic>\n                      variants classified as LP\/P (69.0%), 18 variants classified as VUS (20.7%), while 9 variants were classified as LB\/B (10.3%). Genotype-phenotype correlation was performed among 104 patients with LP\/P variants: 51 cancer cases were recorded in 41 patients and a distinct PHTS phenotype was observed in 25% of patients, with macrocephaly being present in 99% of patients with a known head circumference. Twenty-three patients had neurodevelopmental delay and\/or autism, and we observed an increased prevalence of missense variants in these patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We identified 87 different\n                      <jats:italic>PTEN<\/jats:italic>\n                      variants, and application of\n                      <jats:italic>PTEN<\/jats:italic>\n                      gene-specific ACMG guidelines led to reclassification of 32 variants (36.8%), underscoring the importance of regular variant reassessment using the most recent gene-specific guidelines, ensuring optimal patient management and surveillance.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2026-111772","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T17:20:17Z","timestamp":1788974417000},"page":"jmg-2026-111772","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Phenotypic manifestations and variant reclassification of germline\n                    <i>PTEN<\/i>\n                    variants: a nationwide Danish study"],"prefix":"10.1136","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7624-5318","authenticated-orcid":false,"given":"Annette Lyngholm","family":"Sandsdalen","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics, Rigshospitalet, Copenhagen, Capital Region of Denmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0916-4517","authenticated-orcid":false,"given":"Anne Marie","family":"Jelsig","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Rigshospitalet, Copenhagen, Capital Region of Denmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgitte","family":"Bertelsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Capital Region of Denmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Lohse","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Zealand University Hospital Roskilde, Roskilde, Region Zealand, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabeth Hogh","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Lillebaelt Hospital - University Hospital of Southern Denmark, Vejle, Region Syddanmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Smerdel","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Lillebaelt Hospital - University Hospital of Southern Denmark, Vejle, Region Syddanmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge Sokilde","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Section of Molecular Diagnostics, Aalborg University Hospital, Aalborg, North Denmark Region, Denmark"},{"name":"Department of Clinical Medicine, Aalborg Universitet, Aalborg, North Denmark Region, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3023-7688","authenticated-orcid":false,"given":"Malene","family":"Lundsgaard","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Aalborg Universitetshospital, Aalborg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lise Lotte","family":"Christensen","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Aarhus Universitetshospital, Aarhus N, Region Midt, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Lautrup","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Central Denmark Region, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7824-2080","authenticated-orcid":false,"given":"Susanne Eriksen","family":"Boonen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Odense University Hospital, Odense, Region Syd, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mads","family":"Thomassen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Odense Universitetshospital, Odense, Region Syd, Denmark"},{"name":"Clinical Genome Center, Department of Clinical Research, University of Southern Denmark, Odense, Region Syddanmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2882-6798","authenticated-orcid":false,"given":"Karin A W","family":"Wadt","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Rigshospitalet, Copenhagen, Capital Region of Denmark, Denmark"},{"name":"Department of Clinical Medicine, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Capital Region of Denmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4635-2653","authenticated-orcid":false,"given":"Thomas van Overeem","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Rigshospitalet, Copenhagen, Capital Region of Denmark, Denmark"},{"name":"Department of Clinical Medicine, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Capital Region of Denmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"2026090910201338000_jmg-2026-111772v1.1","doi-asserted-by":"crossref","first-page":"844","DOI":"10.3390\/cancers11060844","article-title":"PTEN Hamartoma Tumor Syndrome: A Clinical Overview","volume":"11","author":"Pilarski","year":"2019","journal-title":"Cancers (Basel)"},{"key":"2026090910201338000_jmg-2026-111772v1.2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-58-1-136"},{"key":"2026090910201338000_jmg-2026-111772v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/ng0597-64"},{"key":"2026090910201338000_jmg-2026-111772v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.11.013"},{"key":"2026090910201338000_jmg-2026-111772v1.5","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1038\/gim.2012.51","article-title":"Estimate of de novo mutation frequency in probands with PTEN hamartoma tumor syndrome","volume":"14","author":"Mester","year":"2012","journal-title":"Genet Med"},{"key":"2026090910201338000_jmg-2026-111772v1.6","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-052218-125823"},{"key":"2026090910201338000_jmg-2026-111772v1.7","doi-asserted-by":"crossref","first-page":"103873","DOI":"10.1016\/j.ejmg.2020.103873","article-title":"Revised Danish guidelines for the cancer surveillance of patients with Cowden Syndrome","volume":"63","author":"Smerdel","year":"2020","journal-title":"Eur J Med Genet"},{"key":"2026090910201338000_jmg-2026-111772v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23636"},{"key":"2026090910201338000_jmg-2026-111772v1.9","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1016\/j.clineuro.2013.09.001","article-title":"Head circumference: the forgotten tool for hydrocephalus management. 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