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PubMed2026

The1H, 15N and13C backbone resonance assignments of an intrinsically disordered region (124-270) of BRCA1 associated RING domain 1 (BARD1).

The BRCA1-associated RING domain protein 1 (BARD1) is the obligate binding partner of the tumor suppressor breast cancer type 1 susceptibility protein (BRCA1) and plays a critical role in maintaining genome integrity. BARD1 contains structured N- and C-terminal domains that mediate heterodimerization with BRCA1, recognition of chromatin marks, and DNA repair functions. Approximately 40% of BARD1 is intrinsically disordered, particularly in the central region of the protein. This intrinsically disordered region (IDR) engages DNA and key repair proteins such as RAD51, BLM, and WRN. DNA binding through the BARD1 IDR facilitates H2A ubiquitination by the BRCA1-BARD1 complex and is essential for stimulating long-range DNA end resection during homologous recombination, underscoring its role in accurate DNA repair. Despite these insights, structural characterization of the IDR remains limited, leaving questions regarding its functional interplay with BRCA1 and other repair factors unresolved. Here, we report the backbone resonance assignments of a BARD1 IDR construct spanning residues 124-270, providing a foundation for future studies aimed at understanding how the disordered regions of BARD1 interact with various binding partners, and cooperates with itself and BRCA1 to regulate genome stability.

Nuclear Magnetic Resonance, Biomolecular↗

PubMed2026

The 1H, 15N and 13C backbone resonance assignments of an intrinsically disordered region (467-696) of breast cancer type 1 susceptibility protein (BRCA1).

The tumor suppressor protein breast cancer type 1 susceptibility protein (BRCA1) plays a central role in maintaining genome stability through its involvement in DNA damage repair, transcriptional regulation, and cell-cycle control. BRCA1 functions as an obligate heterodimer with its binding partner, the BRCA1-associated RING domain protein 1 (BARD1), to coordinate accurate DNA repair. While the structured N- and C-terminal domains of BRCA1 have been well-characterized, the large central region encoded largely by exon 11 that comprises ~ 80% of the protein, is intrinsically disordered, and remains poorly structurally characterized. This intrinsically disordered region (IDR) harbors critical interaction interfaces for key proteins involved in genome maintenance, including RAD50, RAD51, MYC, and RB. Here, we report the backbone resonance assignments of a BRCA1 IDR construct spanning residues 467-696, providing a foundation for future studies aimed at understanding how the disordered central region of BRCA1 contributes to homologous recombination, interactions with BARD1, and overall BRCA1 tumor suppressor function.

BRCA1 Protein↗

PubMed2026

Genomic Landscape of 6597 Hong Kong HBOC Patients: Implications for Beyond-BRCA Multi-Gene Panel Testing and Cancer Surveillance.

Breast cancer remains highly prevalent, where the lifetime risk before age 75 is one in 13. However, known genetic factors were only identified in 14.7% of cases in our Hong Kong Hereditary Breast Cancer Family Registry. Our current local policy for genetic testing does not cover the detection of beyond BRCA1/2. Here we highlight the clinical value of extending testing to beyond BRCA susceptibility genes for improved prevention, diagnosis, and management. We recruited 6597 hereditary breast and ovarian cancer (HBOC) patients from our registry based on family history and clinical criteria. Germline mutations were identified by multi-gene sequencing analysis using next-generation sequencing (NGS). Clinical-pathological characteristics of BRCA and beyond BRCA carriers were compared and the real-world management and surveillance services adopted in Hong Kong were highlighted. In this multi-gene hereditary cancer cohort, germline mutations were identified in 10.9% of cases for BRCA1/2 and 3.5% for beyond BRCA susceptibility genes. These beyond BRCA mutations constitute a considerable proportion of actionable hereditary risk. Notably, PALB2 emerged as the most prevalent non-BRCA gene, followed by TP53, ATM, and BARD1. New cancers or recurrences were detected during their surveillance; the overall pick up rates were 8.3% (PALB2), 29.4% (TP53), 33.3% (PTEN) and 5.6% (BARD1). This study provides the first comprehensive characterization of the beyond BRCA germline landscape in a Hong Kong hereditary cancer cohort and highlights the current need for implementing multi-gene sequencing analysis and surveillance services for HBOC patients, establishing the predominant non-BRCA drivers and providing a robust empirical basis for expanding public genetic screening frameworks.

Humans↗

PubMed2025

Established Cancer Predisposition Genes in Single and Multiple Cancer Diagnoses.

IMPORTANCE: Much of the understanding of cancer risk associated with rare pathogenic variants (RPVs) is derived from family-based studies or clinically ascertained samples, which may be limited by ascertainment and selection bias. OBJECTIVE: To quantify associations between RPVs in previously implicated cancer predisposition genes and single and multiple cancer diagnoses in a large population-based study. DESIGN, SETTING, AND PARTICIPANTS: In this genetic association study, whole-exome sequencing data were used from the UK Biobank, a UK population-based cohort that enrolled participants aged 40 to 69 years between 2006 and 2010. Participants who were involved in the whole-exome sequencing release of 200 000 genomes in 2020 were included in this study. This analysis included White participants only, as findings in other racial and ethnic groups had small sample sizes. Participants were diagnosed before or after biobank enrollment until March 2024. EXPOSURES: The sequencing data of a set of 96 previously implicated cancer predisposition genes were analyzed and compared using 2 methods. To determine the statistical significance of an association, a robust optimal sequence kernel association test was used, while odds ratios (ORs) and 95% CIs were obtained through Firth logistic regression. MAIN OUTCOMES AND MEASURES: The primary study outcome was the diagnosis of 1 of 11 cancers (bladder, breast, central nervous system, colorectal, lung, melanoma, ovary, pancreatic, prostate, renal, thyroid) defined by relevant diagnosis codes in inpatient hospital diagnosis, cancer registry, and/or death registry data. RESULTS: Data from 183 627 participants (101 414 [55.2%] female) were analyzed, including 25 824 participants with at least 1 cancer diagnosis, of whom 23 704 (91.8%) had a single cancer diagnosis and 2130 (8.2%) had 2 or more cancer diagnoses. A total of 157 793 controls had no cancer diagnosis. The median (IQR) age was 62 (56-65) years in participants with at least 1 cancer diagnosis, compared to 57 (50-63) years in those without a cancer diagnosis. Genetic variation in 16 genes was significantly associated with at least 1 cancer of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDKN2A, CHEK2, HOXB13, MITF, MLH1, MSH2, MSH6, NF1, PALB2, RAD51C, and RAD51D). The presence of an RPV in 1 of these 16 genes was associated with increased odds of at least 1 cancer (OR, 1.87; 95% CI, 1.76-1.98) and multiple primary cancers (OR, 2.56; 95% CI, 2.18-2.99). Carrier frequency was 6.28% and 8.36%, respectively. CONCLUSIONS AND RELEVANCE: This genetic association study demonstrates several established associations between cancer predisposition genes and cancer diagnoses in an unselected population-based study. These results also demonstrate that RPVs in cancer predisposition genes are associated with multiple primary cancer diagnoses, suggesting that multigene panel testing may be warranted in these individuals.

Humans↗

PubMed2026

A Novel BRCA1 Pathogenic Variant in Tunisian Patient With High Grade Ovarian Cancer: Favorable Therapeutic Response to Olaparib.

BACKGROUND: Ovarian cancer is one of the leading causes of death from gynecological cancer worldwide. Genetic mutations in genes involved in key cellular functions such as BRCA1/2 play a central role in tumorigenesis and have major implications for targeted therapeutic strategies, especially the use of poly (ADP-ribose) polymerase (PARP) inhibitors. CASE: Herein, we described a case of a 50-year-old woman diagnosed with severe anemia secondary to heavy menometrorrhagia. Initial gynecological evaluation, including transvaginal ultrasound, was unremarkable, and endometrial biopsy was not indicated. Imaging revealed no ovarian abnormalities; however, exploratory laparotomy identified a peritoneal nodule, leading to further investigation. Targeted NGS was performed on somatic and germline DNA samples and showed a frame shift deletion of 10 bp (c.1256_1265del: p.R419Ter) in the BRCA1 gene. This variant, identified only in tumor tissues, is novel and classified as pathogenic in ClinVar and ACMG databases. Additional somatic alterations were detected in TP53 and MSH6, while germline testing revealed only a variant of uncertain significance in BARD1. After first-line chemotherapy, the patient benefited from olaparib and achieved a progression-free survival of 23 months with good tolerance and no evidence of disease recurrence. CONCLUSION: This finding highlights the importance of integrating tumor-based genomic profiling with germline testing to identify actionable mutations and guide precision oncology. The identification of a novel somatic BRCA1 mutation expands the mutational spectrum of HGSOC and underscores the need to include underrepresented populations, such as those from North Africa, in genomic studies.

Humans↗

PubMed2026

Optimizing GRIDSS for clinical use: A targeted NGS filtering strategy for germline structural variant detection.

Detecting intermediate-sized structural variants (SVs) remains challenging in diagnostics, as tools for single-nucleotide and copy-number variants, particularly read-depth-based methods, are often insufficient. GRIDSS addresses this gap by integrating paired-end mapping, split-read analysis, and assembly-based approaches. However, its use in targeted sequencing and diagnostic workflows remains complex. NGS panel data from 9726 patients with suspected hereditary cancer were analyzed using GRIDSS. A filtering strategy was developed to prioritize clinically relevant germline SVs. Multiple parameter settings were tested to optimize performance. The initial dataset of 1,307,592 variants was reduced to 89 candidates after applying the selected filtering strategy. Of these, 24 had been previously detected by routine callers and were not further analyzed. Among the remaining 65, 13 were considered likely true positives after visual inspection using IGV. Experimental validation was performed by Sanger/Nanopore long-read sequencing for these variants, all of which were confirmed. Eight were classified as (likely) pathogenic, including two frameshift duplications in MSH6, one splicing variant in BARD1, and five mobile element insertions in APC, BRCA2, and PALB2. Altogether, GRIDSS implementation increased diagnostic yield while maintaining feasibility for diagnostic workflows. Comprehensive workflow scheme for germline structural variant detection and results in our diagnostic setting.

Humans↗

PubMed2024

Adult-Onset Cancer Predisposition Syndromes in Children and Adolescents-To Test or not to Test?

With the increasing use of comprehensive germline genetic testing of children and adolescents with cancer, it has become evident that pathogenic variants (PV) in adult-onset cancer predisposition genes (aoCPG) underlying adult-onset cancer predisposition syndromes, such as Lynch syndrome or hereditary breast and ovarian cancer, are enriched and reported in 1% to 2% of children and adolescents with cancer. However, the causal relationship between PVs in aoCPGs and childhood cancer is still under investigation. The best-studied examples include heterozygous PVs in mismatch repair genes associated with Lynch syndrome in children with mismatch repair deficient high-grade glioma, heterozygous PVs in BARD1 in childhood neuroblastoma, and heterozygous PVs in BRCA2 in children with rhabdomyosarcoma. The low penetrance for pediatric cancers is considered to result from a combination of the low baseline risk of cancer in childhood and the report of only a modest relative risk of disease in childhood. Therefore, we do not advise that healthy children empirically be tested for PVs in an aoCPG before adulthood outside a research study. However, germline panel testing is increasingly being performed in children and adolescents with cancer, and exome and genome sequencing may be offered more commonly in this population in the future. The precise pediatric cancer risks and spectra associated with PVs in aoCPGs, underlying cellular mechanisms and somatic mutational signatures, as well as treatment response, second neoplasm risks, and psycho-oncological aspects require further research.

Adolescent↗

PubMed2026

Comprehensive Genomic Profiling Reveals the Mutational Spectrum and Clinical Significance of BRCA1/2 and Other Cancer-Susceptibility Genes in Breast Cancer Patients from Southern Tunisia.

BACKGROUND/OBJECTIVES: This study aims to investigate the mutational spectrum of BRCA1 and BRCA2 genes in a cohort of breast cancer (BC) patients from southern Tunisia, and to evaluate their clinical and prognostic significance. Additionally, this study explores the contribution of other cancer predisposition genes and the prevalence of variants of uncertain significance (VUS). RESULTS: Among the 165 patients included, pathogenic or likely pathogenic variants (P/LPVs) in BRCA1/BRCA2 were identified in 19 cases (11.51%), including 8 in BRCA1 and 11 in BRCA2. The presence of BRCA P/LPVs associated with young patients (p = 0.006) and those with TNBC (p = 0.036). Beyond BRCA1/2, PV/LPVs were detected in other cancer-related genes, including TP53 (n = 3), CHEK2, RAD50 (n = 2 cases each), and MUTYH, BARD1, and BRIP1 (one case each). Furthermore, 56 VUS were identified; among them, 7 were prioritized based on in silico predictive analyses, suggesting a potential deleterious effect. However, these VUS should not be used for clinical decision-making without additional evidence from functional and familial segregation studies. CONCLUSIONS: Our findings provide novel insights into the genetic landscape of breast cancer in southern Tunisia, highlighting the clinical relevance of BRCA1/2 mutations and the contribution of other susceptibility genes. These results support the personalized management of breast cancer patients and the implementation of expanded multigene panel testing in routine clinical practice to improve genetic counseling.

BRCA1↗