The promising expectations about personalized medicine have opened the path to routine large-scale sequencing and increased the importance of genetic counseling for hereditary cancers, among which hereditary breast and ovary cancers (HBOC) have a major impact. High-throughput sequencing, or Next-Generation Sequencing (NGS), has improved cancer patient management, ameliorating diagnosis and treatment decisions. In addition to its undeniable clinical utility, NGS is also unveiling a large number of variants that we are still not able to clearly define and classify, the variants of uncertain significance (VUS), which account for about 40% of total variants. At present, VUS use in the clinical context is challenging. Medical reports may omit this kind of data and, even when included, they limit the clinical utility of genetic information. This has prompted the scientific community to seek easily applicable tests to accurately classify VUS and increase the amount of usable information from NGS data. In this review, we will focus on NGS and classification systems for VUS investigation, with particular attention on HBOC-related genes and in vitro functional tests developed for ameliorating and accelerating variant classification in cancer.

中文翻译：

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高通量基因组测序时代不确定意义的变体：乳腺癌和卵巢癌的教训。

对个性化医学的希望寄予了希望，这为常规大规模测序开辟了道路，并增加了遗传咨询对遗传性癌症的重要性，其中遗传性乳腺癌和卵巢癌（HBOC）产生了重大影响。高通量测序或下一代测序（NGS）改善了癌症患者的管理，改善了诊断和治疗决策。除了具有不可否认的临床用途外，NGS还推出了许多我们仍无法清晰定义和分类的变体，不确定性显着（VUS）变体，约占总变体的40％。目前，在临床环境中使用VUS具有挑战性。医学报告可能会忽略此类数据，即使包含在内，它们也会限制遗传信息的临床用途。这促使科学界寻求易于应用的测试来对VUS进行准确分类，并增加NGS数据中可用信息的数量。在这篇综述中，我们将重点研究用于VUS研究的NGS和分类系统，特别关注HBOC相关基因以及为改善和加速癌症变异分类而开发的体外功能测试。