CHEK2 Gene, Full Gene Analysis
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Li-Fraumeni syndrome (LFS) is a rare autosomal dominant hereditary cancer syndrome associated with germline mutations in the TP53 (also p53) gene. LFS is predominantly characterized by sarcoma (osteogenic, chondrosarcoma, rhabdomyosarcoma), young-onset breast cancer, brain cancer (glioblastoma), hematopoietic malignancies, and adrenocortical carcinoma in affected individuals. LFS is highly penetrant; the risk for developing an invasive cancer is 50% by age 30 and 90% by age 70 with many individuals developing multiple primary cancers. Childhood cancers are also frequently observed and typically include soft-tissue sarcomas, adrenocortical tumors, and brain cancer. Other reported malignancies include melanoma, Wilms tumor, kidney tumors, gonadal germ cell tumor, pancreatic cancer, gastric cancer, choroid plexus cancer, colorectal cancer, prostate cancer, endometrial cancer, esophageal cancer, lung cancer, ovarian cancer, and thyroid cancer. Germline mutations in the CHEK2 gene have also been described in families with Li-Fraumeni-like (LFL) syndrome, which is characterized by similar tumor types but is associated with less stringent clinical criteria than Li-Fraumeni syndrome.
Several studies have demonstrated an increased risk for breast cancer associated with founder mutations in CHEK2 (eg, c.1100delC). Two recent studies, a large association study(1) and a meta-analysis,(2) demonstrated an odds ratio of 2.7 to 3.6 for breast cancer in unselected breast cancer patients (without a family history) and an odds ratio of 4.8 to 5.0 for individuals with a family history of breast cancer in a first- and second-degree relative. This suggests a moderate increase in breast cancer risk in women with a truncating CHEK2 mutation without a family history of breast cancer. These studies also suggest that truncating CHEK2 mutations are modifiers of breast cancer risk in the context of a positive family history of breast cancer. Some studies have also suggested an increased risk for colorectal cancer associated with germline CHEK2 mutations; however other studies have suggested that CHEK2 is not a major contributory to colorectal cancer risk.
Evaluation for hereditary susceptibility to breast cancer or Li-Fraumeni-like syndrome
Identification of a familial CHEK2 mutation to allow for predictive testing in family members
All detected alterations are evaluated according to American College of Medical Genetics recommendations.(3) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Some individuals who have an inherited susceptibility to breast cancer and other cancers may have a mutation in CHEK2 that is not identified by this method (eg, deep intronic mutations, promoter mutations). The absence of a mutation, therefore, does not eliminate the possibility of an inherited susceptibility to breast or other cancers. For predictive testing of asymptomatic individuals, it is important to first document the presence of a CHEK2 gene mutation in an affected family member.
In some cases, DNA alterations of undetermined significance may be identified.
We strongly recommend that asymptomatic patients undergoing predictive testing receive genetic counseling both prior to testing and after results are available.
Predictive testing of an asymptomatic child is not recommended.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories at 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Cybulski C, Wokolorcyzk D, Jakubowska A, et al: Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol 2011;29:3747-3752
2. Weischer M, Bojesen SE, Ellervik C, et al: CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 2008;26:542-548
3. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008:10(4):294-300
4. Lindor NM, McMaster ML, Lindor CJ, et al: Concise handbook of familial cancer susceptibility syndromes. Second edition. J Natl Cancer Inst Monogr 2008;(38):1-93