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<p>As gene-panels expand to include candidate breast cancer predisposing genes (CPGs) involved in diverse DNA repair pathways, we investigated an index breast cancer (BC) case from 56 <i>BRCA1/BRCA2</i> implicated high-risk hereditary BC families using gene-based approach for co-occurring, rare germline variants predicted to be damaging and clinically relevant in 276 DNA repair genes (DRGs). Using whole exome sequencing analyses, we identified a total of 287 variants in 55% of DRGs, of which 24 loss-of-function and 36 other predicted damaging variants were identified in 72% and 76% of <i>BRCA1</i> and <i>BRCA2</i> implicated cases, respectively. We also identified 60 variants of clinical interest in various known CPGs, including those involved in risk to other cancers, in 72% of <i>BRCA1</i> and 60% of <i>BRCA2</i> cases. The number of variants predicted to be deleterious in diverse DRGs raises questions about the interpretability of findings as panel testing expands beyond clinically established breast CPGs.</p>

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Co-occurring rare germline DNA repair gene variants in BRCA1/BRCA2 implicated hereditary breast cancer families

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月5日

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  • Wejdan M. Alenezi,
  • Neil Recio,
  • Caitlin T. Fierheller,
  • Corinne Serruya,
  • Timothée Revil,
  • Anne-Marie Mes-Masson,
  • Diane Provencher,
  • Celia M. T. Greenwood,
  • Jiannis Ragoussis,
  • Patricia N. Tonin

摘要

As gene-panels expand to include candidate breast cancer predisposing genes (CPGs) involved in diverse DNA repair pathways, we investigated an index breast cancer (BC) case from 56 BRCA1/BRCA2 implicated high-risk hereditary BC families using gene-based approach for co-occurring, rare germline variants predicted to be damaging and clinically relevant in 276 DNA repair genes (DRGs). Using whole exome sequencing analyses, we identified a total of 287 variants in 55% of DRGs, of which 24 loss-of-function and 36 other predicted damaging variants were identified in 72% and 76% of BRCA1 and BRCA2 implicated cases, respectively. We also identified 60 variants of clinical interest in various known CPGs, including those involved in risk to other cancers, in 72% of BRCA1 and 60% of BRCA2 cases. The number of variants predicted to be deleterious in diverse DRGs raises questions about the interpretability of findings as panel testing expands beyond clinically established breast CPGs.