{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T22:58:55Z","timestamp":1790290735541,"version":"4.1.0"},"reference-count":15,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Hum Genet"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Comprehensive genomic profiling (CGP) using tumor-only sequencing detects pathogenic or likely pathogenic (P\/LP) variants in hereditary cancer susceptibility genes (HCSGs). However, interpreting the biological origin and clinical significance of detected variants is often challenging, complicating communication and decision-making during genetic counseling. We developed a variant allele frequency (VAF)\u2013Tumor Content Graph as a simple visual framework that integrates VAF and tumor content with theoretical reference lines based on the Knudson two-hit hypothesis to support variant interpretation and clinical discussion. We retrospectively reviewed patients who underwent CGP using both tumor-only and tumor\u2013normal paired panels between 2018 and 2025. P\/LP variants in HCSGs recommended for disclosure by the institutional expert panel were plotted on the graph. Among 103 patients, 35 were confirmed to have germline P\/LP variants. Among\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    variants, LOH was observed in 12 of 22 hereditary breast and ovarian cancer (HBOC)-associated tumors and in 2 of 5 non-HBOC tumors. Among other HCSGs, four of eight cases harbored two P\/LP variants distributed along theoretical lines corresponding to germline and somatic alterations. Overall, 18 of 35 cases (51%) showed patterns consistent with the two-hit model. In tumors with mismatch-repair deficiency in one patient and\n                    <jats:italic>POLE<\/jats:italic>\n                    mutations in two patients, multiple variants clustered along the somatic line. The VAF\u2013Tumor Content Graph provides a practical visual framework for interpreting HCSG variants by illustrating potential germline or somatic origin and underlying tumorigenic mechanisms, and may facilitate communication and shared decision-making during genetic counseling.\n                  <\/jats:p>","DOI":"10.1038\/s10038-026-01494-7","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T07:09:31Z","timestamp":1785308971000},"page":"651-657","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["VAF\u2013tumor content graph: a simple visual framework for interpreting hereditary cancer variants and supporting genetic counseling in tumor-only sequencing"],"prefix":"10.1038","volume":"71","author":[{"given":"Mina","family":"Kashima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Tsubamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chinatsu","family":"Kinjo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiho","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiko","family":"Muroi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mako","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiichiro","family":"Otsuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kozo","family":"Kataoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3462-253X","authenticated-orcid":false,"given":"Masayuki","family":"Nagahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuo","family":"Matsuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8997-464X","authenticated-orcid":false,"given":"Hideaki","family":"Sawai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kijima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Miyazaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"1494_CR1","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.annonc.2022.12.003","volume":"34","author":"Z Kuzbari Bandlimits C, Loveday C, Ga","year":"2023","unstructured":"Kuzbari Z, Bandlimits C, Loveday C, Garrett A, Mehine M, George A, et al. Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations. Ann Oncol. 2023;34:215\u201327.","journal-title":"Ann Oncol"},{"key":"1494_CR2","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/s10038-024-01294-x","volume":"70","author":"S Shimada","year":"2025","unstructured":"Shimada S, Yamada T, Minamoto A, Matsukawa M, Yabe I, Tada H, et al. Nationwide survey of the secondary findings in cancer genomic profiling: survey including liquid biopsy. J Hum Genet. 2025;70:33\u201340.","journal-title":"J Hum Genet"},{"key":"1494_CR3","doi-asserted-by":"publisher","first-page":"2599","DOI":"10.1200\/JCO.24.00662","volume":"42","author":"N Tung","year":"2024","unstructured":"Tung N, Ricker C, Messersmith H, Balma\u00f1a J, Domchek S, Martinez Stoffel E, et al. Selection of germline genetic testing panels in patients with cancer: ASCO guideline. 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Int J Clin Oncol. 2022;27:1256\u201363.","journal-title":"Int J Clin Oncol"},{"key":"1494_CR6","unstructured":"ICGC\/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature. 2020;578:82\u201393."},{"key":"1494_CR7","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1200\/JCO.18.00696","volume":"37","author":"MU Salvador","year":"2019","unstructured":"Salvador MU, Truelson MRF, Mason C, Souders B, LaDuca H, Dougall B, et al. Comprehensive paired tumor\/germline testing for Lynch syndrome: bringing resolution to the diagnostic process. J Clin Oncol. 2019;37:647\u201357.","journal-title":"J Clin Oncol"},{"key":"1494_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.gore.2020.100563","volume":"32","author":"K Inoue","year":"2020","unstructured":"Inoue K, Tsubamoto H, Ueda T, Tajima C, Nakagomi N. Recurrent uterine serous carcinoma with a germline pathogenic BRCA2 variant treated using olaparib: a case report. 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Pan-cancer analysis of BRCA1 and BRCA2 genomic alterations and their association with genomic instability as measured by genome-wide loss of heterozygosity. JCO Precis Oncol. 2020;4:442\u201365.","DOI":"10.1200\/PO.19.00345"}],"container-title":["Journal of Human Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s10038-026-01494-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s10038-026-01494-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s10038-026-01494-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T22:03:41Z","timestamp":1790287421000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s10038-026-01494-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,29]]},"references-count":15,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["1494"],"URL":"https:\/\/doi.org\/10.1038\/s10038-026-01494-7","relation":{},"ISSN":["1434-5161","1435-232X"],"issn-type":[{"value":"1434-5161","type":"print"},{"value":"1435-232X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,29]]},"assertion":[{"value":"30 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 June 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 June 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"This study was approved by the Institutional Review Board of Hyogo Medical University (no. 5152). Written informed consent was obtained from all participants (or their legal guardians, where applicable).","order":2,"name":"Ethics","label":"Human ethics","group":{"name":"EthicsHeading","label":"Ethics"}}]}}