CHEK2-Related Cancer Risk

The CHEK2 gene plays role in cell regulation. Certain changes (mutations) in the CHEK2 gene are associated with an increased risk of cancer.

The CHEK2 gene is classified as a “moderate risk” gene, meaning that there is a modestly increased risk for certain types of cancers.  For example, women who have one CHEK2 pathogenic gene mutation have a relative risk of approximately 3 for breast cancer compared to the general population. CHEK2 gene mutations have also been linked to an increased risk for colon cancer and prostate cancer.  Further research is needed to understand the interactions of moderate risk genes and family history on lifetime cancer risk.


CHEK2 cancer screening and risk-reducing options

There is currently no agreement within the medical community on the best long-term medical management for an individual who carries a mutation in the CHEK2 gene.  Healthcare providers oftentimes rely on an individual’s personal and family history to guide medical care. NCCN currently recommends women at age 40 with mutations in CHEK2 undergo annual mammogram and consider annual breast MRI with contrast. There are no data on the benefit of risk reducing mastectomy for women with CHEK2 mutations but this procedure may be considered based on family history.

In regard to colon cancer screening for CHEK2 mutation carriers the NCCN recommends unaffected individuals with a first degree relative with colon cancer that colonoscopy screening occur every five years, beginning at age 40 or 10 years prior to age of the first degree relative age at colon cancer diagnosis. For individuals unaffected with colon cancer and no first degree relative with colon cancer: colonoscopy screening should take place every five years starting at age 40.

Depending upon personal and family history, some men may consider increased prostate cancer surveillance such as PSA blood testing and digital rectal examination.

As research continues to evolve, physicians and researchers will gain a better understanding of how a CHEK2 gene mutation will guide medical care.  Because the information provided to patients will almost certainly change, those with a CHEK2 gene mutation are encouraged to keep in touch with their medical providers in order to receive updates.


CHEK2 testing in other family members

At this point in time, testing adult family members for a moderate risk gene mutation does NOT provide the same clarity or guidance that testing for a high risk gene mutation does. This is because moderate risk gene mutations should not be assumed to be the sole explanation for a particular family’s history of cancer.  For example, a family could have additional undetected/ unknown genetic and/or non-genetic risk factors contributing to the development of cancer seen in family members.  It is recommended that concerned family members discuss the issue of testing and screening with their physicians.  However, given the current lack of data regarding CHEK2 gene mutations, if an adult family member were to test negative for a familial CHEK2 gene mutation, that individual may still be at increased risk for cancer depending upon the family history and possibility for other genes to be playing a role in that individual/ family.  Cancer screening should be performed in accordance with the family history until further data is available.


Significance of pathogenic or likely pathogenic change in CHEK2

When pathogenic (harmful) or likely pathogenic (likely harmful) changes (mutations) are detected in CHEK2, this information is informative in 4 ways:

  1. Diagnostics: It might have contributed to a cancer developing and provides part of an explanation as to why someone develops cancer.
  2. Prevention: If identified in other family members, early screening or risk reductive surgical planning might be indicated and pursued. Evidenced based counseling framework related literature.
  3. Therapeutics: The CHEK2 gene produces a protein in the body essential for repair of cells and if this function is altered, a cell may be unstable and develop into a cancer. Specific medications are being studied as part of clinical trials for people with an inability to appropriately repair their DNA due to changes in CHEK2 and other DNA damage related genes. gov.
  4. Family Planning: Some individuals and families may decide to use genetic information for planning a family.  It is important to know for individuals carrying a pathogenic mutation in CHEK2 there is a 50% chance the change may be shared between siblings and passed on to the next generation.

Variant of Uncertain Significance (VUSs) in the CHEK2 gene

In order for a change in a gene to be determined as pathogenic or likely pathogenic significant evidence or burden of proof is needed given the importance of decisions and recommendations to be made, therefore variants of uncertain significance which have not met this burden of proof should not guide recommendations.


Data Repositories for CHEK2 Variants

The federal government is invested in learning more about variants of uncertain significance and tracking these variants in a central source called ClinVar.  However, significant expertise and curation is required before variants are deposited in this central source. PROMPT is dedicated to generating quality data.

The consequences of misclassification can be significant and costly when individuals make life impacting decisions.  Recently, the PROMPT study team illustrated in work spearheaded by Balamana et al. how different variants may be classified and the potential consequences of mis-classification based on the 4 main uses of this information by individuals and providers.



More information on the CHEK2 gene:

  1. Gene Information:   OMIM: 604373 , GeneTests , Orphanet , DECIPHER
  2. Where to send testing:  GeneTests
  3. Catalogue of mutations:  ClinVar. 
  4. Registry information: Genetic Testing Registry 2. Apostolou P, Fostira F. Hereditary breast cancer: the era of new susceptibility genes. Biomed Res Int 2013;2013:747318. 4. Kuusisto KM, Bebel A, Vihinen M, et al. Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals. Breast Cancer Res 2011;13:R20. 6. 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. 8. CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet 2004;74:1175–1182. 10. Han FF, Guo CL, Liu LH. The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a meta-analysis. DNA Cell Biol 2013;32:329– 335. 12. Pritchard CC, Mateo J, Walsh MF, et al: Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 375:443-53, 2016
  5. 11.Tung N, Domchek SM, Stadler Z, Nathanson KL, Couch F, Garber JE, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol. 2016;13(9):581-8. doi: 10.1038/nrclinonc.2016.90. PubMed PMID: 27296296.
  6. 9. Schmidt MK, Hogervorst F, van Hien R, et al. Age- and tumor subtype-specific breast cancer risk estimates for CHEK2*1100delC carriers. J Clin Oncol 2016;34:2750–2760.
  7. 7. Naslund-Koch C, Nordestgaard BG, Bojesen SE. Increased risk for other cancers in addition to breast cancer for CHEK2*1100delC heterozygotes estimated from the Copenhagen General Population Study. J Clin Oncol 2016;34:1208–1216.
  8. 5. Cybulski C, Wokolorczyk 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.
  9. 3. Iniesta MD, Gorin MA, Chien LC, et al. Absence of CHEK2*1100delC mutation in families with hereditary breast cancer in North America. Cancer Genet Cytogenet 2010;202:136–140.
  10. 1. Walsh MF, Nathanson KL, Couch FJ, Offit K. Adv Exp Med Biol. 2016;882:1-32. Genomic Biomarkers for Breast Cancer Risk. doi: 10.1007/978-3-319-22909-6