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INTERNATIONAL CONGRESS OF

CancerGenetics

• Application of bioinformatics tools for the detection of germline BRCA1/BRCA2 variants in diagnostic NGS data: A Systematic Review

• Hediye Ahouei,^1,* Sajad Dehnavi ,²
  1. Department of Laboratory Sciences, School of Paramedical and Rehabilitation Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
  2. Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  
  
  
• Introduction: Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 markedly increase the lifetime risk of breast and ovarian cancer to 40–66% and 13–46%, respectively. Therefore, identifying germline pathogenic variants (GPVs) in these genes is crucial for the early diagnosis and management of high-risk individuals and patients with cancer, as well as for risk assessment. However, while advancements in next-generation sequencing (NGS) and other new DNA sequencing techniques have facilitated genomic diagnostics, extensive sequencing data cannot be processed or interpreted effectively without sophisticated bioinformatics pipelines and tools. Thus, the purpose of this systematic review is to evaluate current bioinformatics approaches for detecting BRCA1/2 variants in diagnostic NGS data.
• Methods: Multiple databases, including PubMed, Google Scholar, Scopus, and Web of Science, were searched using the terms "BRCA1", "BRCA2", "bioinformatics tool", "in silico", "variant calling", "next-generation sequencing (NGS)", and "germline variant" to find articles published between 2023 and 2025. The search was limited to clinical studies and cross-sectional analyses involving human samples that employed bioinformatics tools or pipelines to detect germline BRCA1/2 variants in diagnostic NGS data. Duplicate and irrelevant articles were excluded.
• Results: A total of 25 studies were collected, of which 10 met the inclusion criteria and were finally analyzed. Nine studies employed NGS as the primary sequencing method, and one study used whole exome sequencing (WES). Multiplex ligation-dependent probe amplification (MLPA) was used as a confirmatory test in four studies. Various bioinformatics tools, including variant callers (NextGENe and Geneticist Assistant), annotation platforms (ANNOVAR, VEP, and Snpeff), and prediction tools (Missense3D and PROVEAN), were employed across the included studies to analyze next-generation sequencing (NGS) data and detect pathogenic germline variants. They also used several databases, including COSMIC, ClinVar, HGMD, dbSNP, ExAC, and gnomAD, to identify pathogenic mutations. Two studies discovered a total of 56 novel pathogenic variants in the BRCA genes using multiple in silico tools, including SIFT, PolyPhen, CADD, Mutation Taster, REVEL, and the EVE class method. One study showed that researchers developed a mass spectrometry-based method (MALDI-TOF MS) that is effective, sensitive, and rapid for primary screening of copy number variations (CNVs) in BRCA genes. The MS assay demonstrated greater sensitivity than targeted NGS (100% versus 75%). A Canadian study reported a 7.3% prevalence of GPVs, 5.3% of which were in the BRCA1/2/PALB2 genes. Another study demonstrated that using whole exome sequencing (WES) in ovarian cancer considerably improved variant detection rates and identified novel predisposing genes beyond BRCA1/2. Additionally, scientists developed three new tools: BRACNAC, which detects CNVs with 100% sensitivity and 94% specificity; HerediVar, which offers modular annotation services; and HerediClassify, which is a variant classification algorithm. Moreover, an automated, reproducible pipeline was developed using Nextflow to process and evaluate the pathological significance of the identified genetic variants. This pipeline incorporates two variant callers, Strelka and DeepVariant, which have efficient run times.
• Conclusion: About 5% of women with breast cancer and 10-20% of those with ovarian cancer have a harmful variant of the BRCA1/2 gene. Significant progress in genetic diagnostics and advanced bioinformatics tools in recent years has facilitated more efficient data analysis. Newly developed tools, such as BRACNAC, HerediClassify, and HerediVar, have improved CNV detection and classification. Furthermore, in silico analyses have identified novel pathogenic variants in the BRCA genes that are not mentioned in existing databases. These advancements improve the detection and interpretation of relevant variants, enabling earlier diagnoses, averting millions of future cancer diagnoses, and saving many lives worldwide. Therefore, further studies are needed to develop efficient bioinformatics tools and improve current approaches to uncover novel pathogenic variants and advance the processing of sequencing data.
• Keywords: BRCA1, BRCA2, next-generation sequencing (NGS), pathogenic variants, bioinformatics