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Rare genetic variants: making the connection with breast cancer susceptibility

机译：罕见的遗传变异：与乳腺癌易感性有关

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The practice of clinical genetics in the context of breast cancer predisposition has reached another critical point in its evolution. For the past two decades, genetic testing offered to women attending clinics has been limited to BRCA1 and BRCA2 unless other syndromic indicators have been evident (e.g. PTEN and TP53 for Cowden and Li-Fraumeni syndrome, respectively). Women (and their families) who are concerned about their personal and/or family history of breast and ovarian cancer have enthusiastically engaged with clinical genetics services, anticipating a genetic cause for their cancer predisposition will be identified and to receive clinical guidance for their risk management and treatment options. Genetic testing laboratories have demonstrated similar enthusiasm for transitioning from single gene to gene panel testing that now provide opportunities for the large number of women found not to carry mutations in BRCA1 and BRCA2 , enabling them to undergo additional genetic testing. However, these panel tests have limited clinical utility until more is understood about the cancer risks (if any) associated with the genetic variation observed in the genes included on these panels. New data is urgently needed to improve the interpretation of the genetic variation data that is already reported from these panels and to inform the selection of genes included in gene panel tests in the future. To address this issue, large internationally coordinated research studies are required to provide the evidence-base from which clinical genetics for breast cancer susceptibility can be practiced in the era of gene panel testing and oncogenetic practice. Two significant steps associated with this process include i) validating the genes on these panels (and those likely to be added in the future) as bona fide breast cancer predisposition genes and ii) interpreting the variation, on a variant-by-variant basis in terms of their likely “pathogenicity” ― a process commonly referred to as “variant classification” that will enable this new genetic information to be used at an individual level in clinical genetics services. Neither of these fundamental steps have been achieved for the majority of genes included on the panels. We are thus at a critical point for translational research in breast cancer clinical genetics ― how can rare genetic variants be interpreted such that they can be used in clinical genetics services and oncogenetic practice to identify and to inform the management of families that carry these variants?.
机译：乳腺癌易感性背景下的临床遗传学实践已达到其发展的另一个关键点。在过去的二十年中，除非有其他综合症候指标明显（例如，分别针对Cowden和Li-Fraumeni综合征的PTEN和TP53），否则向门诊妇女提供的基因检测仅限于BRCA1和BRCA2。关注乳腺癌和卵巢癌的个人和/或家族史的妇女（及其家庭）积极参与临床遗传学服务，预计会发现其易患癌症的遗传原因，并接受其风险管理的临床指导和治疗选择。基因检测实验室显示出从单一基因到基因组检测的类似热情，现在为大量发现未携带BRCA1和BRCA2突变的女性提供了机会，使她们能够接受其他基因检测。但是，这些小组测试在临床上的应用有限，直到人们对与这些小组所含基因中观察到的遗传变异有关的癌症风险（如果有的话）有了更多的了解。迫切需要新的数据来改善对这些小组已经报告的遗传变异数据的解释，并为将来在基因小组测试中选择的基因提供信息。为了解决这个问题，需要进行大规模的国际协调研究，以提供证据基础，从而可以在基因组检测和致癌基因实践时代实践乳腺癌易感性的临床遗传学。与该过程相关的两个重要步骤包括：i）验证这些面板上的基因（以及将来可能添加的那些基因），作为真正的乳腺癌易感基因，以及ii）在每个变体的基础上解释变异它们可能的“致病性”的术语，即通常称为“变异分类”的过程，它将使这一新的遗传信息能够在临床遗传学服务的个人水平上使用。对于面板上包括的大多数基因，这些基本步骤均未实现。因此，我们处于乳腺癌临床遗传学转化研究的关键时刻-如何解释稀有的遗传变异，以便将其用于临床遗传服务和致癌基因实践中，以识别并告知携带这些变异的家庭管理？ 。

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