Scholarlink

<p>Hereditary breast cancer involves multiple risk genes, including <i>BARD1</i>, which confers low to moderate risk and is associated with triple-negative breast cancer (TNBC). We report a proband with a primary ER+/PR+/HER2- breast cancer, which recurred unilaterally as a TNBC and who later developed endometrial cancer. Clinical germline testing revealed a rare <i>BARD1</i> missense variant of uncertain significance [c.2258G&gt;T; p.(Gly753Val)]. Whole-exome sequencing of tumors and blood revealed <i>BARD1</i> loss of heterozygosity and mutational signature 3 – indicative of homologous recombination (HR) repair deficiency – exclusively in the TNBC recurrence. Functional assays demonstrated impaired HR repair <i>via</i> increased PARP inhibitor sensitivity and reduced RAD51 foci formation. We hypothesize that the selective pressure exerted by tamoxifen resulted in breast cancer subtype switching and uncovered the pathogenic potential of the <i>BARD1</i> p.(Gly753Val) variant. This case illustrates a previously unreported scenario where the pathogenicity of a germline <i>BARD1</i> variant appears conditional on prior treatment.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Multimodal analysis of a rare BARD1 missense variant suggests its pathogenicity is conditional

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月21日

查看全文
  • Fiona Chan-Pak-Choon,
  • Yuandi Gao,
  • José Camacho-Valenzuela,
  • Júlia-Jié Cabré-Romans,
  • Amisha Minju-OP,
  • Lili Fu,
  • Paz Polak,
  • Barbara Rivera,
  • Raquel Cuella-Martin,
  • William D. Foulkes

摘要

Hereditary breast cancer involves multiple risk genes, including BARD1, which confers low to moderate risk and is associated with triple-negative breast cancer (TNBC). We report a proband with a primary ER+/PR+/HER2- breast cancer, which recurred unilaterally as a TNBC and who later developed endometrial cancer. Clinical germline testing revealed a rare BARD1 missense variant of uncertain significance [c.2258G>T; p.(Gly753Val)]. Whole-exome sequencing of tumors and blood revealed BARD1 loss of heterozygosity and mutational signature 3 – indicative of homologous recombination (HR) repair deficiency – exclusively in the TNBC recurrence. Functional assays demonstrated impaired HR repair via increased PARP inhibitor sensitivity and reduced RAD51 foci formation. We hypothesize that the selective pressure exerted by tamoxifen resulted in breast cancer subtype switching and uncovered the pathogenic potential of the BARD1 p.(Gly753Val) variant. This case illustrates a previously unreported scenario where the pathogenicity of a germline BARD1 variant appears conditional on prior treatment.