CHEK2 variants: linking functional impact to cancer risk

Protein-truncating variants in the breast cancer susceptibility gene CHEK2 are associated with a moderately increased risk of breast cancer. By contrast, for missense variants of uncertain significance (VUS) in CHEK2 the associated breast cancer risk is often unclear. To facilitate their classification, functional assays that determine the impact of missense VUS on CHK2 protein function have been performed. Here we discuss these functional analyses that consistently reveal an association between impaired protein function and increased breast cancer risk. Overall, these findings suggest that damaging CHEK2 missense VUS are associated with a risk of breast cancer similar to that of protein-truncating variants. This indicates the urgency of expanding the functional characterization of CHEK2 missense VUS to further understand the associated cancer risk.

Automated summary

Protein-truncating variants in the breast cancer susceptibility gene CHEK2 are associated with an increased risk of breast cancer, while the risk associated with missense variants of uncertain significance is often unclear. Functional assays have been conducted to determine the impact of missense variants on CHK2 protein function, consistently revealing an association between impaired function and increased breast cancer risk. These findings indicate the urgency of expanding the functional characterization of CHEK2 missense variants to further understand the associated cancer risk.