Purpose

Although CHEK2 is a well-established cancer gene, questions remain including whether risks vary substantially between different variants and whether biallelic carriers have higher risks than heterozygotes. We report on a cohort of individuals with CHEK2 pathogenic and likely pathogenic variants (collectively, PV) in order to better characterize this gene.

Methods

We retrospectively queried samples submitted for multi-gene hereditary cancer testing to identify individuals with CHEK2 PVs and assessed differences in phenotypes among various genotypes.

Results

CHEK2 PVs were identified in 2508 individuals, including 32 individuals with biallelic CHEK2 PVs. Breast (female, 59.9% and male, 11.8%), prostate (20.1%), and colorectal (3.5%), were among the most frequently reported cancers. Select missense PVs showed similar cancer prevalence to truncating PVs while some others showed lower prevalence. No significant differences were observed between biallelic carriers and heterozygotes.

Conclusions

Our data support that some, but not all, CHEK2 missense PVs demonstrate lower cancer prevalence; further studies are needed to continue characterizing possible variant specific risks. In addition, biallelic CHEK2 PVs do not appear to be associated with a more severe phenotype than single CHEK2 PVs. Furthermore, co-occurrences with PVs in other cancer risk genes are common among CHEK2 heterozygotes and often warrant additional management.

中文翻译：

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通过多基因面板测试确定的CHEK2携带者的癌症患病率差异。

目的

尽管CHEK2是一个公认的癌症基因，但仍然存在疑问，包括不同变体之间的风险是否显着不同，以及双等位基因携带者的风险是否高于杂合子。我们报告了一组具有CHEK2致病性和可能致病性变异体（统称为PV）的个体，以更好地表征该基因。

方法

我们回顾性地查询了提交给多基因遗传性癌症测试的样本，以识别具有CHEK2 PV的个体，并评估了各种基因型之间的表型差异。

结果

在2508名个体中鉴定出CHEK2 PV，其中32名具有双等位基因CHEK2 PV。乳腺癌（女性占59.9％，男性11.8％），前列腺癌（20.1％）和结直肠癌（3.5％）是最常报告的癌症。精选的错义PV显示出与截短PV相似的癌症患病率，而另一些显示出较低的患病率。在双等位基因携带者和杂合子之间没有观察到显着差异。

结论

我们的数据支持一些（但不是全部）CHEK2错义病毒显示出较低的癌症患病率。需要进一步研究以继续表征可能的变体特定风险。另外，双等位基因CHEK2 PV似乎没有比单个CHEK2 PV更严重的表型。此外，CHEK2杂合子在其他癌症风险基因中与PV共存是常见现象，通常需要额外的管理。