For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
0
views
68
references
 Top references
cited by
0
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      72
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Uncovering the clinical relevance of unclassified variants in DNA repair genes: a focus on BRCA negative Tunisian cancer families

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Introduction: Recent advances in sequencing technologies have significantly increased our capability to acquire large amounts of genetic data. However, the clinical relevance of the generated data continues to be challenging particularly with the identification of Variants of Uncertain Significance (VUSs) whose pathogenicity remains unclear. In the current report, we aim to evaluate the clinical relevance and the pathogenicity of VUSs in DNA repair genes among Tunisian breast cancer families.

          Methods: A total of 67 unsolved breast cancer cases have been investigated. The pathogenicity of VUSs identified within 26 DNA repair genes was assessed using different in silico prediction tools including SIFT, PolyPhen2, Align-GVGD and VarSEAK. Effects on the 3D structure were evaluated using the stability predictor DynaMut and molecular dynamics simulation with NAMD. Family segregation analysis was also performed.

          Results: Among a total of 37 VUSs identified, 11 variants are likely deleterious affecting ATM, BLM, CHEK2, ERCC3, FANCC, FANCG, MSH2, PMS2 and RAD50 genes. The BLM variant, c.3254dupT, is novel and seems to be associated with increased risk of breast, endometrial and colon cancer. Moreover, c.6115G>A in ATM and c.592+3A>T in CHEK2 were of keen interest identified in families with multiple breast cancer cases and their familial cosegregation with disease has been also confirmed. In addition, functional in silico analyses revealed that the ATM variant may lead to protein immobilization and rigidification thus decreasing its activity. We have also shown that FANCC and FANCG variants may lead to protein destabilization and alteration of the structure compactness which may affect FANCC and FANCG protein activity.

          Conclusion: Our findings revealed that VUSs in DNA repair genes might be associated with increased cancer risk and highlight the need for variant reclassification for better disease management. This will help to improve the genetic diagnosis and therapeutic strategies of cancer patients not only in Tunisia but also in neighboring countries.

          Related collections

          Most cited references68

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          The Sequence Alignment/Map format and SAMtools

          Heng Li, Bob Handsaker, Alec Wysoker … (2009)
          Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk
          Article 0 comments Cited 13722 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Fast and accurate short read alignment with Burrows–Wheeler transform

            Heng Li, Richard Durbin (2009)
            Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ∼10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: http://maq.sourceforge.net Contact: rd@sanger.ac.uk
            Article 0 comments Cited 10240 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

              Sue Richards, Nazneen Aziz, Sherri Bale … (2015)
              The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.
              Article 0 comments Cited 7076 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Maroua Boujemaa: URI : https://loop.frontiersin.org/people/956852/overviewRole: Role: Role: Role: Role: Role: Role: Role: Role:
                Fatma Nouira: URI : https://loop.frontiersin.org/people/2557901/overviewRole: Role: Role: Role:
                Nouha Jandoubi: Role: Role:
                Nesrine Mejri: URI : https://loop.frontiersin.org/people/1126033/overviewRole: Role:
                Hanen Bouaziz: URI : https://loop.frontiersin.org/people/1902004/overviewRole: Role:
                Cherine Charfeddine: URI : https://loop.frontiersin.org/people/2112024/overviewRole:
                Sonia Ben Nasr: URI : https://loop.frontiersin.org/people/957319/overviewRole: Role:
                Soumaya Labidi: Role: Role:
                Houda El Benna: URI : https://loop.frontiersin.org/people/1126178/overviewRole: Role:
                Yosra Berrazega: Role: Role:
                Haifa Rachdi: Role: Role:
                Nouha Daoud: Role: Role:
                Farouk Benna: Role: Role:
                Abderrazek Haddaoui: URI : https://loop.frontiersin.org/people/1125673/overviewRole: Role:
                Sonia Abdelhak: URI : https://loop.frontiersin.org/people/42850/overviewRole: Role: Role:
                Mohamed Samir Boubaker: Role: Role: Role:
                Hamouda Boussen: URI : https://loop.frontiersin.org/people/1126078/overviewRole: Role: Role:
                Yosr Hamdi: URI : https://loop.frontiersin.org/people/954975/overviewRole: Role: Role: Role: Role: Role: Role: Role:
                Journal
                Journal ID (nlm-ta): Front Genet
                Journal ID (iso-abbrev): Front Genet
                Journal ID (publisher-id): Front. Genet.
                Title: Frontiers in Genetics
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-8021
                Publication date (Electronic): 19 January 2024
                Publication date Collection: 2024
                Volume: 15
                Electronic Location Identifier: 1327894
                Affiliations
                [1] 1 Laboratory of Biomedical Genomics and Oncogenetics , LR20IPT05 , Institut Pasteur de Tunis , University of Tunis El Manar , Tunis, Tunisia
                [2] 2 Laboratory of Bioactive Substances , Center of Biotechnology of Borj Cedria , University of Tunis El Manar , Hamam, Tunisia
                [3] 3 Medical Oncology Department , Abderrahman Mami Hospital , Faculty of Medicine Tunis , University Tunis El Manar , Tunis, Tunisia
                [4] 4 Surgical Oncology Department , Salah Azaiez Institute of Cancer , Tunis, Tunisia
                [5] 5 High Institute of Biotechnology of Sidi Thabet , Biotechpole of Sidi Thabet , University of Manouba , Ariana, Tunisia
                [6] 6 Department of Medical Oncology , Military Hospital of Tunis , Tunis, Tunisia
                [7] 7 Radiation Oncology Department , Salah Azaiez Institute , Tunis, Tunisia
                [8] 8 Laboratory of Human and Experimental Pathology , Institut Pasteur de Tunis , Tunis, Tunisia
                Author notes

                Edited by: Stephen J. Bush, Xi’an Jiaotong University, China

                Reviewed by: Magdalena Ratajska, University of Otago, New Zealand

                Vignesh Ravichandran, Memorial Sloan Kettering Cancer Center, United States

                *Correspondence: Maroua Boujemaa, maroua.boujemaa@ 123456pasteur.utm.tn ; Yosr Hamdi, yosr.hamdi@ 123456pasteur.utm.tn
                Article
                Publisher ID: 1327894
                DOI: 10.3389/fgene.2024.1327894
                PMC ID: 10834681
                PubMed ID: 38313678
                SO-VID: 6a7481ab-cb7a-491c-aaed-19bb69d969ab
                Copyright © Copyright © 2024 Boujemaa, Nouira, Jandoubi, Mejri, Bouaziz, Charfeddine, Ben Nasr, Labidi, El Benna, Berrazega, Rachdi, Daoud, Benna, Haddaoui, Abdelhak, Samir Boubaker, Boussen and Hamdi.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 25 October 2023
                Date accepted : 02 January 2024
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Tunisian Ministry of Higher Education and Scientific Research (LR16IPT05 and LR20IPT05) and the Tunisian Ministry of Health (PEC-4-TUN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Genetics
                Subject: Original Research
                Custom metadata
                section-at-acceptance Human and Medical Genomics

                ScienceOpen disciplines: Genetics
                Keywords: variants of uncertain significance,clinical relevance,dna repair genes,breast cancer,pathogenicity predictions,segregation analysis
                Data availability:
                ScienceOpen disciplines: Genetics
                Keywords: variants of uncertain significance, clinical relevance, dna repair genes, breast cancer, pathogenicity predictions, segregation analysis

                Comments

                Comment on this article