Improving the efficiency of determining "variants of unknown significance" detected by cancer genome testing - Proposing a new evaluation framework useful for considering diagnosis and treatment strategies -

• Variants of unknown significance (VUS) detected in large numbers in cancer genome testing(*1)= Genetic changes whose relationship to cancer is not clear" will be analyzed by computer to create a system to prioritize candidates for diagnosis and treatment.
• By clarifying the pathological significance of these VUS through research, it is expected that they will be applied to the selection of more appropriate cancer treatments and the risk assessment of hereditary tumors.
   

With the spread of cancer genomic testing, pathogenic variants useful for treatment are being identified.(*2)A major issue is that while a large number of variants are detected, many times as many variants of unknown significance (VUS), which are difficult to interpret, are detected.
Teru Nakahara, a specially appointed academic researcher at Hiroshima University Hospital's Department of Medical Genetics, and colleagues are involved in the selection of effective therapeutic drugs such as platinum agents and PARP inhibitors, which are the causative genes of hereditary breast and ovarian cancer (HBOC).BRCA1/2gene(*3)We focused on VUS.
Comprehensive cancer genome profiling (CGP) of 2172 cases at Hiroshima University Hospital (cancer genome medical center hospital) and 12 affiliated facilities(*4)Analyze test results and use computer to predict pathogenicity (in silicoanalysis(*5)) evaluated the impact of each variant on gene function. Based on the results, we constructed an evaluation framework that prioritizes the extraction of candidates that will lead to future functional analysis.
The results of this research were published in the European Journal of Human Genetics (Q1), the official journal of the European Society of Human Genetics, with support from Hiroshima University for article publication fees.

Magazine: European Journal of Human Genetics (published March 2, 2026)

Paper title: A Prioritization Framework forBRCA1/2Variants of Uncertain Significance Identified by Comprehensive Genomic Profiling

author:Hikaru Nakahara1, Hiroaki Niitsu1＊, Asuka Toshida1, Keisuke Goto2, Masami Yamauchi3, Khilola Saipova1, C. Nelson Hayes4, Nobuyuki Hinata2, Shiro Oka4, Takao Hinoi1
1. Hiroshima University Hospital Genetics Department
2. Department of Urology, Hiroshima University Graduate School of Medical Sciences
3. Prefectural Hiroshima Hospital Clinical Oncology Department
4. Department of Gastroenterology, Hiroshima Graduate School of Medical Sciences
*Corresponding author
DOI: 10.1038/s41431-026-02058-1

In recent years, the spread of comprehensive cancer genomic profiling (CGP) has made it possible to comprehensively analyze genomic abnormalities in cancer, and treatment selection based on genomic abnormalities such as genetic variants has become possible for various cancer types.
　
On the other hand, many of the detected variants are "variants of unknown significance (VUS)," and their clinical significance is unclear, posing major challenges in their interpretation and clinical application. Although VUS is generally not treated as a pathogenic variant, it may actually contain mutations that affect the function of the gene.
　
　BRCA1/2is an important gene that is directly linked to the selection of effective therapeutic drugs such as platinum drugs and PARP inhibitors, and is also the causative gene of hereditary breast and ovarian cancer (HBOC). Evaluation of its pathogenicity is important for determining treatment strategies, diagnosing hereditary tumor syndromes, and analyzing relatives. With the widespread use of CGP, many cases have been reported not only from HBOC-related tumors but also from non-HBOC-related tumors.BRCA1/2While variants are detected, many VUSs are also detected, and interpretation of their pathogenicity is a clinical challenge.

Against this background, this studyBRCA1/2Focusing on genes, we aimed to build a framework to efficiently extract variants that are likely to have clinical significance from VUS and link them to experimental functional analysis.

In both cases of this variant, platinum-based anticancer drugs or PARP inhibitors were found to have a high therapeutic effect, and this type of VUS re-evaluation framework is considered to be an example that can lead to actual treatment.

We plan to investigate whether the framework for VUS reevaluation developed in this study can be applied to other genetic tumor syndromes and genetic diseases.

Also,in silicoWe will continue our efforts at Hiroshima University Hospital to incorporate analysis into daily cancer genome treatment and improve the accuracy of VUS interpretation.

In the future, clarifying the clinical significance of VUS is expected to lead to expanded treatment options and appropriate surveillance and genetic counseling for hereditary tumors.

(*1) Variant of unknown significance (VUS)
Previously, the term "genetic mutation" was used to refer to changes in the base sequence of a gene, but since it does not necessarily cause disease, the term "variant" is now used as a neutral term. Variants whose relationship to disease is unclear are called VUS.

(*2) Pathogenic variant
Among variants, this refers to those that are clearly involved in the onset of the disease.

(*3)BRCA1/2variant
BRCA1/2 has the function of repairing DNA damage. When this function breaks down, genetic damage increases, resulting in the development of cancer.BRCA1/2Pathogenic variants are particularly found in breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer, and are also a criterion for selecting therapeutic agents.

(*4) Comprehensive cancer genome profiling (CGP)
A test that comprehensively analyzes numerous cancer-related genes from cancer tissue and cancer patient plasma.

(*5)in silico
A method of performing simulation and data analysis using a computer

(*6) Splicing abnormality
When making proteins based on genetic information, the parts that serve as templates are joined together one after another. This is called splicing. When this splicing becomes abnormal, a normal template cannot be formed by correct splicing, resulting in the production of proteins that do not have normal functions.