Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.


The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Your Environment. Your Health.

Publication Detail

Title: Response to DNA damage of CHEK2 missense mutations in familial breast cancer.

Authors: Roeb, Wendy; Higgins, Jake; King, Mary-Claire

Published In Hum Mol Genet, (2012 Jun 15)

Abstract: Comprehensive sequencing of tumor suppressor genes to evaluate inherited predisposition to cancer yields many individually rare missense alleles of unknown functional and clinical consequence. To address this problem for CHEK2 missense alleles, we developed a yeast-based assay to assess in vivo CHEK2-mediated response to DNA damage. Of 25 germline CHEK2 missense alleles detected in familial breast cancer patients, 12 alleles had complete loss of DNA damage response, 8 had partial loss and 5 exhibited a DNA damage response equivalent to that mediated by wild-type CHEK2. Variants exhibiting reduced response to DNA damage were found in all domains of the CHEK2 protein. Assay results were in agreement with epidemiologic assessments of breast cancer risk for those variants sufficiently common for case-control studies to have been undertaken. Assay results were largely concordant with consensus predictions of in silico tools, particularly for damaging alleles in the kinase domain. However, of the 25 variants, 6 were not consistently classifiable by in silico tools. An in vivo assay of cellular response to DNA damage by mutant CHEK2 alleles may complement and extend epidemiologic and genetic assessment of their clinical consequences.

PubMed ID: 22419737 Exiting the NIEHS site

MeSH Terms: Amino Acid Sequence; Breast Neoplasms/genetics*; Case-Control Studies; Cell Cycle Proteins/genetics; Checkpoint Kinase 2; DNA Damage*; Family Health; Female; Genetic Complementation Test; Humans; Male; Molecular Sequence Data; Mutation, Missense*; Pedigree; Protein-Serine-Threonine Kinases/genetics*; Saccharomyces cerevisiae Proteins/genetics; Saccharomyces cerevisiae/genetics; Saccharomyces cerevisiae/growth & development; Sequence Homology, Amino Acid

to Top