Interpretive Handbook

Test 61479 :
CHEK2 Gene, Known Mutation

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 contributor to colorectal cancer risk.


Note: This test is appropriate for predictive testing in families in which a point mutation or small insertion/deletion/duplication has been identified. SDEL / Single-Gene Large Deletion and Duplication Analysis is appropriate for predictive testing in families in which a large deletion or duplication (whole exon or multi-exon) has been identified. If a familial mutation has not been previously identified, CHEKS / CHEK2 Gene, Full Gene Analysis is more appropriate.

Useful For Suggests clinical disorders or settings where the test may be helpful

Predictive testing for breast cancer susceptibility in which a point mutation or small insertion/deletion/duplication mutation in the CHEK2 gene has been identified in an affected family member

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

The identification of a disease-causing mutation in an affected family member is necessary before predictive testing for other family members can be performed. If a familial mutation has not been previously identified, order CHEKS / CHEK2 Gene, Full Gene Analysis.


Analysis is performed for the familial mutation provided only. This assay does not rule out the presence of other mutations within this gene or within other genes that may be associated with hereditary cancer syndromes.


We strongly recommend that 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.


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Any error in the diagnosis or in the pedigree provided to us, including false paternity, could lead to erroneous interpretation of results.


A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories at 800-533-1700 for instructions for testing patients who have received a bone marrow transplant.

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