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<p>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)–Tumor 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–normal 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 <i>BRCA1/2</i> 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 <i>POLE</i> mutations in two patients, multiple variants clustered along the somatic line. The VAF–Tumor 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.</p>

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VAF–tumor content graph: a simple visual framework for interpreting hereditary cancer variants and supporting genetic counseling in tumor-only sequencing

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Mina Kashima,
  • Hiroshi Tsubamoto,
  • Tomoko Ueda,
  • Chinatsu Kinjo,
  • Chiho Okada,
  • Yoshiko Muroi,
  • Mako Ueda,
  • Taiichiro Otsuki,
  • Kozo Kataoka,
  • Masayuki Nagahashi,
  • Ikuo Matsuda,
  • Hideaki Sawai,
  • Takashi Kijima,
  • Ayako Miyazaki

摘要

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)–Tumor 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–normal 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 BRCA1/2 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 POLE mutations in two patients, multiple variants clustered along the somatic line. The VAF–Tumor 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.