AUTHOR=Boujemaa Maroua , Nouira Fatma , Jandoubi Nouha , Mejri Nesrine , Bouaziz Hanen , Charfeddine Cherine , Ben Nasr Sonia , Labidi Soumaya , El Benna Houda , Berrazega Yosra , Rachdi Haifa , Daoud Nouha , Benna Farouk , Haddaoui Abderrazek , Abdelhak Sonia , Samir Boubaker Mohamed , Boussen Hamouda , Hamdi Yosr 

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

JOURNAL=Frontiers in Genetics

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1327894

DOI=10.3389/fgene.2024.1327894

ISSN=1664-8021

ABSTRACT=<p><bold>Introduction:</bold> 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.</p><p><bold>Methods:</bold> 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 <italic>in silico</italic> 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.</p><p><bold>Results:</bold> Among a total of 37 VUSs identified, 11 variants are likely deleterious affecting <italic>ATM, BLM, CHEK2, ERCC3, FANCC, FANCG, MSH2, PMS2 and RAD50</italic> genes. The <italic>BLM</italic> variant, c.3254dupT, is novel and seems to be associated with increased risk of breast, endometrial and colon cancer. Moreover, c.6115G&gt;A in <italic>ATM</italic> and c.592+3A&gt;T in <italic>CHEK2</italic> 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 <italic>in silico</italic> analyses revealed that the <italic>ATM</italic> variant may lead to protein immobilization and rigidification thus decreasing its activity. We have also shown that <italic>FANCC</italic> and <italic>FANCG</italic> variants may lead to protein destabilization and alteration of the structure compactness which may affect FANCC and FANCG protein activity.</p><p><bold>Conclusion:</bold> 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.</p>