Genes Tested: CHEK2
Tests Offered: Ambry SEQUENCE™, Gene Sequence Analysis, Specific Mutation Analysis
Checkpoint Kinase 2 (CHEK2) is a serine/threonine kinase involved in cell cycle regulation and apoptosis after DNA damage has occurred. Activation of CHEK2 as a result of DNA damage inhibits a cell from initiating mitosis. Evidence to date suggests that signals from damaged DNA is transmitted to CHEK2 via ataxia telangiectasia mutated (ATM). Known substrates of CHEK2 include BRCA1, BRCA2, and p53; they have been implicated in cellular processes responsible for the maintenance of genomic stability.
Recent studies have identified founder mutations in CHEK2 that confer an increased cancer risk among certain ethnic groups. The 3 most common founder mutations in the CHEK2 gene are c.1100delC, c.444+1G>A (also known as IVS2+1G>A), and I157T (c.470T>C). The 1100delC mutation, a protein truncating mutation located with the kinase domain, is reported to abolish the kinase activity of CHEK2. It is most commonly seen among individuals of Eastern European descent, less commonly seen among Southern European and non-white populations. The frequencies of the IVS2+1G>A and del5395 mutations are highest in the Eastern European populations as well.
Multiple studies indicate that mutations in the CHEK2 gene confer an increased risk of developing many types of cancer including breast, prostate, colon, thyroid, and kidney. Carriers with a family history of breast or prostate cancer have a higher risk of developing these cancers than CHEK2 carriers without a family history. Mutations are more likely to be found among women with bilateral versus those with unilateral breast cancers. A female carrier of a CHEK2 mutation has 1% risk per year of developing a second breast primary cancer.
The Ambry Test: CHEK2 detects ~92% of all described mutations.