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Sequence Variants in Breast/Ovarian Cancer Susceptibility Genes: From Risk Assessment...
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Sequence Variants in Breast/Ovarian Cancer Susceptibility Genes: From Risk Assessment to Clinical Management in Carrier Individuals and Their Blood Relatives

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Epidemiology and Prevention".

Deadline for manuscript submissions: 30 June 2026 | Viewed by 5941

Special Issue Editors

Dr. Arcangela De Nicolo

E-Mail
Guest Editor
Institute of Oncology and Molecular Genetics, Riga Stradins University, Riga, Latvia
Interests: hereditary breast/ovarian cancer; BRCA1 and BRCA2 genes; variant classification and reporting; variants of uncertain significance; molecular mechanisms of carcinogenesis; sporadic breast cancer
Dr. Miguel De la Hoya

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Guest Editor
Molecular Oncology Laboratory, IdISSC (San Carlos Biomedical Research Institute), Madrid, Spain
Interests: hereditary breast/ovarian cancer; ATM; BARD1; BRCA1; BRCA2; BRIP1; CHEK2; PALB2; RAD51C; RAD51D; alternative splicing in control populations and variant carriers; ACMG/AMP classification of genetic variants
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Special Issue Information

Dear Colleagues,

Genetic testing for breast/ovarian cancer susceptibility plays a crucial role in personalized medicine. The BRCA1 and BRCA2 genes stand as a model for variant-associated cancer risk assessment and management. The implementation of massively parallel sequencing in cancer genetics has increased the amount of information that needs to be deciphered prior to potential clinical use. The elucidation of the biological and clinical significance of sequence variants—a prerequisite for effective cancer prevention and treatment—can be challenging for certain genes and variant types, thus limiting the clinical value of test results. Transnational collaborative efforts, the collection of multi-layered evidence, and ad hoc in depth analyses are often required to achieve variant classification, which, in turn, informs clinical decision-making.

This Special Issue aims to advance our knowledge of both basic and clinically relevant aspects pertaining to the assessment and management of the cancer risk associated with sequence variants in breast/ovarian cancer susceptibility genes. We welcome original articles and reviews covering a broad spectrum of research topics, including the following:

  • High- and moderate-risk gene variants and the clinical management of carrier individuals and their non-carrier blood relatives;
  • Other cancer phenotypes associated with (likely) pathogenic variants in breast/ovarian cancer susceptibility genes;
  • Uses of PRS for risk refinement (real-world studies on models integrating multiple risk factors are encouraged);
  • Evidence supporting variant classification, e.g., segregation analyses, functional studies, or the characterization of splice-site variants (multifactorial analyses are especially welcome);
  • Molecular mechanisms of response/resistance to platinum and PARP inhibitors;
  • Preventive and therapeutic (surgical and medical) options for carrier individuals.

Dr. Arcangela De Nicolo
Dr. Miguel De la Hoya
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • breast/ovarian cancer susceptibility genes
  • risk assessment and clinical management of carrier individuals and their blood relatives
  • risk models
  • variant classification
  • multifactorial approaches

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Published Papers (3 papers)

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Research

11 pages, 1045 KB  
Article
Processed Transcript Insertion as a Novel Germline Mutational Mechanism in BRCA1-Associated Hereditary Breast Cancer
by Anikó Bozsik, Henriett Butz, Vince Kornél Grolmusz, Petra Nagy, Tímea Pócza, Erika Tóth, Erzsébet Csernák, Attila Patócs and János Papp
Cancers 2025, 17(23), 3872; https://doi.org/10.3390/cancers17233872 - 2 Dec 2025
Viewed by 751
Abstract
Background/Objectives: Germline BRCA1 mutations account for ~15–20% of hereditary breast and ovarian cancer (HBOC) cases. While most are small sequence variants, structural rearrangements also contribute significantly to the pathogenic landscape. Conventional diagnostic workflows often miss such events, underscoring the need for comprehensive [...] Read more.
Background/Objectives: Germline BRCA1 mutations account for ~15–20% of hereditary breast and ovarian cancer (HBOC) cases. While most are small sequence variants, structural rearrangements also contribute significantly to the pathogenic landscape. Conventional diagnostic workflows often miss such events, underscoring the need for comprehensive approaches. Here, we report a previously undescribed pathogenic mechanism—a transposon-mediated processed transcript insertion—expanding the mutational spectrum underlying hereditary breast cancer susceptibility. Methods: The studied case was discovered during our germline genotyping routine: next-generation sequencing followed by library preparation with a custom hereditary cancer panel. The identified variant was validated by orthogonal sequencing and multiplex ligation-dependent probe amplification (MLPA). RNA-level functional assays, including nonsense-mediated decay inhibition, were conducted to assess transcript stability. Constitutional origin was confirmed by analysis of multiple normal tissues, and tumor material was evaluated for loss of heterozygosity (LOH). Results: NGS detected a 700 bp insertion in exon 16 of BRCA1, corresponding to a complete processed transcript of RPL18A. The insertion caused a frameshift and premature stop codon, triggering degradation of the aberrant transcript. The variant was present in multiple somatic tissues, and its heritable nature was further confirmed by genotyping a first-degree relative, who was also found to carry the insertion. Tumor DNA analysis revealed strong LOH with retention of the variant allele. Conclusions: This study identifies, for the first time, a heritable processed transcript insertion as a pathogenic event in BRCA1. Such variants are undetectable by conventional diagnostic workflows lacking structural variant analysis, highlighting the importance of comprehensive approaches for accurate diagnosis and genetic counselling in hereditary cancer syndromes. Full article
(This article belongs to the Special Issue Sequence Variants in Breast/Ovarian Cancer Susceptibility Genes: From Risk Assessment to Clinical Management in Carrier Individuals and Their Blood Relatives)
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19 pages, 3779 KB  
Article
Classification of Gene Variants in a Danish Population with Suspected Predisposition to Hereditary Breast and/or Ovarian Cancer
by Anne K. Munch, Elisabeth S. Feldner, Caroline H. Bækgaard, Mie B. Larsen, Naja Slemming-Adamsen, Desirée S. Boonen, Nanna B. Møller, Inge S. Pedersen, Thomas V. O. Hansen, Thorkild Terkelsen, Mark Burton, Qin Hao, Susanne E. Boonen and Mads Thomassen
Cancers 2025, 17(11), 1819; https://doi.org/10.3390/cancers17111819 - 29 May 2025
Viewed by 1745
Abstract
Background: Gene variants of unknown significance (VUSs) present a challenge in genetic counselling. The primary aim of this study was to describe the spectrum of genetic findings in a cohort of 5923 Danish patients with suspected predisposition to hereditary breast and/or ovarian cancer, [...] Read more.
Background: Gene variants of unknown significance (VUSs) present a challenge in genetic counselling. The primary aim of this study was to describe the spectrum of genetic findings in a cohort of 5923 Danish patients with suspected predisposition to hereditary breast and/or ovarian cancer, with a focus on classifying gene variants and investigating their distribution. Methods: The gene variants were classified using the American College of Medical Genetics (ACMG) guidelines as well as gene-specific guidelines where applicable. The identified VUSs were further examined through association analysis, comparison of the frequencies in this Danish population to those in the Swedish population using gnomAD 2.1, and splice analysis using RNA sequencing. Results: Of 167 variants that were clinically classified as VUSs prior to this research study, 38 (22.8%) were either up- or downgraded based on the guidelines that were used. We found that 630 patients (10.6%) carried a likely pathogenic or pathogenic variant, mainly in BRCA1 (31.9%) and BRCA2 (26.0%). VUSs were carried by 1606 (27.1%) patients, mainly in BARD1 (27.6%) and ATM (19.3%). Our association study assigned criteria for 10 gene variants, while our splice analysis assigned criteria for 3 gene variants but did not reclassify the variants. Conclusions: A total of 22.8% of the 167 variants that were observed in this study and which were previously classified as VUSs in a clinical setting were reclassified in this study. In total, 10.6% of the patients with a suspected predisposition to hereditary breast and/or ovarian cancer carried a likely pathogenic or pathogenic variant. The high incidence of VUSs observed in this study reflects the challenges faced in the daily clinical setting. Full article
(This article belongs to the Special Issue Sequence Variants in Breast/Ovarian Cancer Susceptibility Genes: From Risk Assessment to Clinical Management in Carrier Individuals and Their Blood Relatives)
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14 pages, 3221 KB  
Article
Splicing Dysregulation of Non-Canonical GC-5′ Splice Sites of Breast Cancer Susceptibility Genes ATM and PALB2
by Inés Llinares-Burguet, Lara Sanoguera-Miralles, Alberto Valenzuela-Palomo, Alicia García-Álvarez, Elena Bueno-Martínez and Eladio A. Velasco-Sampedro
Cancers 2024, 16(21), 3562; https://doi.org/10.3390/cancers16213562 - 22 Oct 2024
Cited by 5 | Viewed by 2654
Abstract
Background/Objectives: The non-canonical GC-5′ splice sites (5′ss) are the most common exception (~1%) to the classical GT/AG splicing rule. They constitute weak 5′ss and can be regulated by splicing factors, so they are especially sensitive to genetic variations inducing the misrecognition of [...] Read more.
Background/Objectives: The non-canonical GC-5′ splice sites (5′ss) are the most common exception (~1%) to the classical GT/AG splicing rule. They constitute weak 5′ss and can be regulated by splicing factors, so they are especially sensitive to genetic variations inducing the misrecognition of their respective exons. We aimed to investigate the GC-5′ss of the breast/ovarian cancer susceptibility genes, ATM (exon 50), BRIP1 (exon 1), and PALB2 (exon 12), and their dysregulation induced by DNA variants. Methods: Splicing assays of the minigenes, mgATM_49-52, mgBRIP1_1-2, and mgPALB2_5-12, were conducted to study the regulation of the indicated GC-5′ss. Results: A functional map of the splicing regulatory elements (SRE) formed by overlapping exonic microdeletions revealed three essential intervals, ATM c.7335_7344del, PALB2 c.3229_3258del, and c.3293_3322del, which are likely targets for spliceogenic SRE-variants. We then selected 14 ATM and 9 PALB2 variants (Hexplorer score < −40) located at these intervals that were assayed in MCF-7 cells. Nine ATM and three PALB2 variants affected splicing, impairing the recognition of exons 50 and 12, respectively. Therefore, these variants likely disrupt the active SREs involved in the inclusion of both exons in the mature mRNA. DeepCLIP predictions suggested the participation of several splicing factors in exon recognition, including SRSF1, SRSF2, and SRSF7, involved in the recognition of other GC sites. The ATM spliceogenic variants c.7336G>T (p.(Glu2446Ter)) and c.7340T>A (p.(Leu2447Ter)) produced significant amounts of full-length transcripts (55–59%), which include premature termination stop codons, so they would inactivate ATM through both splicing disruption and protein truncation mechanisms. Conclusions: ATM exon 50 and PALB2 exon 12 require specific sequences for efficient recognition by the splicing machinery. The mapping of SRE-rich intervals in minigenes is a valuable approach for the identification of spliceogenic variants that outperforms any prediction software. Indeed, 12 spliceogenic SRE-variants were identified in the critical intervals. Full article
(This article belongs to the Special Issue Sequence Variants in Breast/Ovarian Cancer Susceptibility Genes: From Risk Assessment to Clinical Management in Carrier Individuals and Their Blood Relatives)
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