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<p>Comprehensive genomic profiling (CGP) has significantly advanced cancer genomics by enabling broad detection of clinically relevant genomic alterations across diverse cancers. In the context of <i>BRCA1/2</i>, CGP has expanded analysis beyond conventional testing for hereditary breast and ovarian cancer (HBOC), thereby identifying otherwise unrecognized variants. Nevertheless, the high prevalence of variants of uncertain significance (VUS) remains a major obstacle to clinical implementation. To address this challenge, we analyzed 2172 CGP tests performed at Hiroshima University Hospital and affiliated institutions in Japan. <i>BRCA1/2</i> VUS identified through CGP were systematically prioritized using an integrative framework combining in silico prediction and functional evidence. From 526 <i>BRCA1/2</i> variants, 153 were classified as VUS. Our variant prioritization filter based on ten in silico predictors narrowed these to 10 candidates, including two splice-site and eight missense variants, most of which were concordant with prior functional studies. Among these, the significance of <i>BRCA2</i>:c.67 G &gt; C (p.D23H, NM_000059.4) had remained unclear. Functional analysis demonstrated exon 2 skipping consistent with loss of function, and clinical observations from two patients carrying this variant showed that therapeutic responses aligned with the biology of homologous recombination deficiency. These findings present a proof-of-concept framework for prioritizing and interpreting <i>BRCA1/2</i> VUS detected in real-world CGP testing. By integrating multiple in silico predictors with functional evidence, this approach enables systematic prioritization and interpretation of <i>BRCA1/2</i> VUS and may be broadly applicable to variant assessment in hereditary cancer predisposition genes.</p><p></p>

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A prioritization framework for BRCA1/2 variants of uncertain significance identified by comprehensive genomic profiling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月2日

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  • Hikaru Nakahara,
  • Hiroaki Niitsu,
  • Asuka Toshida,
  • Keisuke Goto,
  • Masami Yamauchi,
  • Khilola Madaminovna Saipova,
  • C. Nelson Hayes,
  • Nobuyuki Hinata,
  • Shiro Oka,
  • Takao Hinoi

摘要

Comprehensive genomic profiling (CGP) has significantly advanced cancer genomics by enabling broad detection of clinically relevant genomic alterations across diverse cancers. In the context of BRCA1/2, CGP has expanded analysis beyond conventional testing for hereditary breast and ovarian cancer (HBOC), thereby identifying otherwise unrecognized variants. Nevertheless, the high prevalence of variants of uncertain significance (VUS) remains a major obstacle to clinical implementation. To address this challenge, we analyzed 2172 CGP tests performed at Hiroshima University Hospital and affiliated institutions in Japan. BRCA1/2 VUS identified through CGP were systematically prioritized using an integrative framework combining in silico prediction and functional evidence. From 526 BRCA1/2 variants, 153 were classified as VUS. Our variant prioritization filter based on ten in silico predictors narrowed these to 10 candidates, including two splice-site and eight missense variants, most of which were concordant with prior functional studies. Among these, the significance of BRCA2:c.67 G > C (p.D23H, NM_000059.4) had remained unclear. Functional analysis demonstrated exon 2 skipping consistent with loss of function, and clinical observations from two patients carrying this variant showed that therapeutic responses aligned with the biology of homologous recombination deficiency. These findings present a proof-of-concept framework for prioritizing and interpreting BRCA1/2 VUS detected in real-world CGP testing. By integrating multiple in silico predictors with functional evidence, this approach enables systematic prioritization and interpretation of BRCA1/2 VUS and may be broadly applicable to variant assessment in hereditary cancer predisposition genes.