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by CancerConnect Updated 10/2021

Mutations in the CHEK2 gene increase the risk of breast cancer, particularly among women who also have a family history of the disease. 

Up to 10% of breast cancers are hereditary - there are 11 breast cancer predisposition genes with BRCA1 and BRCA2 carrying the highest risk. BRCA1, BRCA2 and PALB2 confer the highest risk of developing breast cancer.

Moderate-risk gene mutations that confer a 20%-30% lifetime risk include ATM and CHEK2. CHEK2 serves the body as a tumor suppressor, but when it’s mutated, it can be linked to cancer, including breast and prostate cancer.

Women carrying the CHEK2 mutation have a moderate risk for developing breast cancer, ranging from 23%-48% depending on their variant and family history and men with CHEK2 have an increased risk of developing prostate cancer.

More than 2,500 variants of CHEK2 exist, with 270 of those classified as likely or definitely disease-causing

What does the research show?

Mutations in the CHEK2 gene have been reported to increase breast cancer risk by up to three-fold. The risk associated with a CHEK2 mutation, however, may vary by a woman’s family history of breast cancer. CHEK2 mutations may increase breast cancer risk to a greater extent among women with a family history of the disease.

To explore the relationships among CHEK2 mutations, family history of breast cancer, and risk of breast cancer, researchers conducted a study in Poland. Information was collected about more than 7,000 women with BRCA1-negative breast cancer and more than 4,000 women without breast cancer.

The researchers considered both first-degree and second-degree family history of breast cancer. First-degree relatives are parents, offspring, and siblings. Second-degree relative are grandparents, grandchildren, aunts and uncles, nephews and nieces, and half siblings.

  • A particular type of CHEK2 mutation (a truncating mutation) was found in 3% of the women with breast cancer and in less than 1% of the women without breast cancer.
  • Among women with a first- or second-degree family history of breast cancer, risk of breast cancer was five times higher among those with a  CHEK2 mutation than among those without a CHEK2 mutation. Among women without a family history of breast cancer, risk of breast cancer was three-times higher among those with a CHEK2 mutation.
  • Assuming a lifetime risk of breast cancer of 6% (the general-population risk seen in Poland; this is lower than what is seen in the United States), the lifetime risk of breast cancer for a woman with a CHEK2 mutation was estimated to be 20% if there was no family history of breast cancer, 28% if one second-degree relative had breast cancer, 34% if one first-degree relative had breast cancer, and 44% if both a first- and second-degree relative had breast cancer.

First-degree relatives of women with a CHEK2 gene mutation and bilateral breast cancer have a high lifetime risk of developing breast cancer themselves, according to a study published in Lancet .

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The CHEK2 gene is believed to play a role in controlling the growth of cells. A particular mutation in the CHEK2 gene, known as 1100delC, inactivates the CHEK2 gene and appears to increase the risk of cancer. This gene mutation is present in an estimated 0.5% to 1.3% of white northern Europeans.

Researchers in the UK conducted a study to assess the risk of breast cancer in family members of women with bilateral breast cancer and the 1100delC mutation of the CHEK2 gene. Four hundred and sixty-nine women with bilateral breast cancer were identified from cancer registries, and seven of these women (1.5%) tested positive for the 1100delC mutation.

Risk of breast cancer was elevated in all first-degree relatives of women with bilateral breast cancer, but risk was greatest if a CHEK2 gene mutation was present.

When the woman with bilateral breast cancer had a CHEK2 mutation, her female first-degree relatives had a risk of breast cancer that was roughly 12-times higher than that of the general population. By the age of 80, 59% of these female relatives were expected to develop breast cancer. Because of the small number study participants with a CHEK2 mutation, it was not possible to estimate risk of breast cancer in male family members.

In contrast, when the woman with bilateral breast cancer did not have a CHEK2 mutation, her female first-degree relatives had a risk of breast cancer that was roughly three-and-one-half-times higher than that of the general population. By the age of 80, 24% of these female relatives were expected to develop breast cancer. Male first-degree relatives also had an increased risk of developing breast cancer.

These results suggest that first-degree relatives of women with bilateral breast cancer have an increased risk of developing breast cancer themselves; the risk is greatest if a CHEK2 gene mutation is present. The researchers note that testing women with a family history of bilateral breast cancer for the 1100delC mutation of the CHEK2 gene may provide important information about their lifetime risk of breast cancer.d

Reference: 

  1. Johnson N, Fletcher O, Naceur-Lombardelli C et al. Interaction Between CHEK2*1100delC and Other Low-Penetrance Breast-Cancer Susceptibility Genes: A Familial Study. Lancet. 2004;366:1554-57.
  2. 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. Journal of Clinical Oncology. Early online publication August 29, 2011.