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

Authors

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

Published in

Journal of human genetics. Jul 29, 2026. Epub Jul 29, 2026.

Abstract

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.

PMID:
42527578
Bibliographic data and abstract were imported from PubMed on 30 Jul 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.