A missense variant effect map for the human tumor-suppressor protein CHK2.

The tumor suppressor CHEK2 encodes the serine/threonine protein kinase CHK2 which, upon DNA damage, is important for pausing the cell cycle, initiating DNA repair, and inducing apoptosis. CHK2 phosphorylation of the tumor suppressor BRCA1 is also important for mitotic spindle assembly and chromosomal stability. Consistent with its cell-cycle checkpoint role, both germline and somatic variants in CHEK2 have been linked to breast and other cancers.

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.

Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk.

Unlabelled: Heterozygous carriers of germline loss-of-function variants in the tumor suppressor gene checkpoint kinase 2 (CHEK2) are at an increased risk for developing breast and other cancers. While truncating variants in CHEK2 are known to be pathogenic, the interpretation of missense variants of uncertain significance (VUS) is challenging. Consequently, many VUS remain unclassified both functionally and clinically.

Characterisation of protein-truncating and missense variants in in 15 768 women from Malaysia and Singapore.

Background: Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 () confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population.

Methods: Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels.

Functional Characterization of Variants of Uncertain Significance: Toward Cancer Risk and Therapy Response Prediction.

In recent years it has become clear that pathogenic variants in are associated with a high risk for breast, ovarian and pancreatic cancer. However, the clinical relevance of variants of uncertain significance (VUS) in , which are increasingly identified through clinical genetic testing, is unclear. Here we review recent advances in the functional characterization of VUS in .