FaCD Online Syndrome Fact Sheet

Last updated: 26 Jul 2013

Name: CHEK2-associated cancer

Synonym: incl. Hereditary Breast and Colorectal Cancer, HBCC

Mode of Inheritance: AD/multifact

OMIM number: 604373  


CHEK2/CHK2, mapped to 22q12.1

Tumor features

breast cancer
colorectal cancer

Tumor features (possible)

lung/bronchial cancer
melanoma, cutaneous
ovarian cancer (i.e. epithelial origin)
ovarian cancer, borderline
prostate cancer
renal cell cancer
thyroid cancer
urinary bladder cancer


Breast Cancer risk
The CHEK2 1100delC mutation has a carrier frequency of approximately 0.7% in Northern and Western European populations. It confers an approximately 2-5 fold increased risk of breast cancer and tenfold increased risk of male breast cancer[1-3,11,16]. For familial breast cancer, this corresponds to a cumulative risk of breast cancer at age 70 years in CHEK2*1100delC heterozygotes of 37% (95% CI, 26% to 56%)[3]. In a more recent study on 7494 BRCA1/2 negative breast cancer patients and over 4000 controls, the breast cancer lifetime risk for carriers of CHEK2 truncating mutations was estimated to be 20% for a woman with no affected relative, 28% for a woman with one second-degree relative affected, 34% for a woman with one first-degree relative affected, and 44% for a woman with both a first- and second-degree relative affected[19].

A significant excess risk for CHEK2 1100delC mutation carriers to develop a contralateral breast tumor has been calculated, OR = 6.5 (95% CI 1.5-28.8, p = 0.005). The highest percentage of mutation carriers was detected among those bilateral breast cancer patients who had received radiation treatment for their first breast cancer[4]. Relatives of bilateral breast cancer cases who are carriers of CHEK2*1100delC appear to have a substantially higher risk of breast cancer (SIR 12.11)[7]. In a Swedish populaton, the 1100delC mutation was found to be most frequent in breast cancer patients diagnosed below 46 yrs of age with a positive family history: 5%, compared to 2% of all breast cancer patients with a positive family history and less than 1% in sporadic breast cancer patients[8]. In a Polish study, the I157T mutation was typically associated with lobular type breast carcinoma[9].

Other Cancers
The CHEK2 1100delC mutation identifies families with clustering of both colorectal and breast cancer, referred to as the hereditary breast and colorectal cancer phenotype(HBCC)[5]. The mutation, however, appears not to be the major contributor to the HBCC phenotype, thus limitimg its use in genetic counseling. Possibly, CHEK2 1100delC acts as a risk modifier in families with Lynch syndrome[18].
In a Swedish study, CHEK2 1100delC was not a major cause of double primary breast and colorectal cancer[6]. In Polish studies, positive associations with protein-truncating CHEK2 alleles were seen for cancers of the thyroid (OR 4.9), breast (OR 2.2), and prostate (OR 2.2). The missense variant I157T was associated with an increased risk of breast cancer (OR 1.4), colon cancer (OR 2.0), kidney cancer (OR 2.1), prostate cancer (OR 1.7), thyroid cancer (OR 1.9) and ovarian cystadenomas, borderline ovarian cancers and low-grade invasive ovarian cancers, but not no high grade ovarian cancer[12,15,17]. All mutation types combined were associated with an increased risk of bladder cancer (OR 1.9)[13]. In a Finnish population, the I157T mutation was observed more frequently in colorectal cancer patients than in controls. A trend towards higher frequency was seen in patients with multiple primary tumors and/or a family history of cancer[14]. A Danish-German study suggested a two-fold increase in melanoma risk for 1100delC carriers[23].

In contrast, in a large multicenter study, the risk of cancers other than breast cancer in female carriers was not significantly elevated, although between ages 20 to 50 years, the risks of colorectal and lung cancer were both higher in female carriers than noncarriers. There was no evidence of a higher prostate cancer risk in carriers than noncarriers[10].

In an Italian study[20], 12 probands from hereditary breast/ovarian cancer families with one case of sarcoma and no detectable mutation in BRCA1, BRCA2, and TP53 genes, were screened for CHEK2 mutations. Two patients were shown to have the c.507delT truncating CHEK2 mutation and one the missense c.38A>G mutation, respectively. The authors speculated that germline CHEK2 mutations might predispose to sarcoma development.

Risk associated with bi-allelic CKEK2 mutations
Women with homozygous 1100delC germline mutations appear to be at a strongly increased breast cancer risk{21,22}. Possibly lung cancer risk is increased as well[21].


[1] Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton D, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber B, Rahman N, Stratton MR, . Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature genetics 2002; 31(1):55-9.
[2] Weischer M, Bojesen SE, Tybjaerg-Hansen A, Axelsson CK, Nordestgaard BG. Increased risk of breast cancer associated with CHEK2*1100delC. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2007; 25(1):57-63.
[3] Weischer M, Bojesen SE, Ellervik C, Tybjaerg-Hansen A, Nordestgaard BG. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008; 26(4):542-8.
[4] Broeks A, de Witte L, Nooijen A, Huseinovic A, Klijn JG, van Leeuwen FE, Russell NS, van't Veer LJ. Excess risk for contralateral breast cancer in CHEK2*1100delC germline mutation carriers. Breast cancer research and treatment 2004; 83(1):91-3.
[5] Meijers-Heijboer H, Wijnen J, Vasen H, Wasielewski M, Wagner A, Hollestelle A, Elstrodt F, van den Bos R, de Snoo A, Fat GT, Brekelmans C, Jagmohan S, Franken P, Verkuijlen P, van den Ouweland A, Chapman P, Tops C, Möslein G, Burn J, Lynch H, Klijn J, Fodde R, Schutte M. The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. American journal of human genetics 2003; 72(5):1308-14.
[6] Isinger A, Bhat M, Borg A, Nilbert M. CHEK2 1100delC in patients with metachronous cancers of the breast and the colorectum. BMC cancer 2006; 6():64.
[7] Johnson N, Fletcher O, Naceur-Lombardelli C, dos Santos Silva I, Ashworth A, Peto J. Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: a familial study. Lancet 2005 Oct 29-Nov 4; 366(9496):1554-7.
[8] Margolin S, Eiberg H, Lindblom A, Bisgaard ML. CHEK2 1100delC is prevalent in Swedish early onset familial breast cancer. BMC cancer 2007; 7():163.
[9] Huzarski T, Cybulski C, Domagala W, Gronwald J, Byrski T, Szwiec M, Woyke S, Narod SA, Lubinski J. Pathology of breast cancer in women with constitutional CHEK2 mutations. Breast cancer research and treatment 2005; 90(2):187-9.
[10] Thompson D, Seal S, Schutte M, McGuffog L, Barfoot R, Renwick A, Eeles R, Sodha N, Houlston R, Shanley S, Klijn J, Wasielewski M, Chang-Claude J, Futreal PA, Weber BL, Nathanson KL, Stratton M, Meijers-Heijboer H, Rahman N, Easton DF. A multicenter study of cancer incidence in CHEK2 1100delC mutation carriers. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2006; 15(12):2542-5.
[11] CHEK2 breast cancer case-control consortium. CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. American journal of human genetics 2004; 74(6):1175-82.
[12] Cybulski C, Wokolorczyk D, Kladny J, Kurzawski G, Kurzwaski G, Suchy J, Grabowska E, Gronwald J, Huzarski T, Byrski T, Górski B, D Ecedil Bniak T, Narod SA, Lubinski J. Germline CHEK2 mutations and colorectal cancer risk: different effects of a missense and truncating mutations?. European journal of human genetics : EJHG 2007; 15(2):237-41.
[13] Zlowocka E, Cybulski C, Górski B, Debniak T, Slojewski M, Wokolorczyk D, Serrano-Fernández P, Matyjasik J, van de Wetering T, Sikorski A, Scott RJ, Lubinski J. Germline mutations in the CHEK2 kinase gene are associated with an increased risk of bladder cancer. International journal of cancer. Journal international du cancer 2008; 122(3):583-6.
[14] Kilpivaara O, Alhopuro P, Vahteristo P, Aaltonen LA, Nevanlinna H. CHEK2 I157T associates with familial and sporadic colorectal cancer. Journal of medical genetics 2006; 43(7):e34.
[15] Cybulski C, Górski B, Huzarski T, Masojc B, Mierzejewski M, Debniak T, Teodorczyk U, Byrski T, Gronwald J, Matyjasik J, Zlowocka E, Lenner M, Grabowska E, Nej K, Castaneda J, Medrek K, Szymanska A, Szymanska J, Kurzawski G, Suchy J, Oszurek O, Witek A, Narod SA, Lubinski J. CHEK2 is a multiorgan cancer susceptibility gene. American journal of human genetics 2004; 75(6):1131-5.
[16] Zhang S, Phelan CM, Zhang P, Rousseau F, Ghadirian P, Robidoux A, Foulkes W, Hamel N, McCready D, Trudeau M, Lynch H, Horsman D, De Matsuda ML, Aziz Z, Gomes M, Costa MM, Liede A, Poll A, Sun P, Narod SA. Frequency of the CHEK2 1100delC mutation among women with breast cancer: an international study. Cancer research 2008; 68(7):2154-7.
[17] Szymanska-Pasternak J, Szymanska A, Medrek K, Imyanitov EN, Cybulski C, Gorski B, Magnowski P, Dziuba I, Gugala K, Debniak B, Gozdz S, Sokolenko AP, Krylova NY, Lobeiko OS, Narod SA, Lubinski J. CHEK2 variants predispose to benign, borderline and low-grade invasive ovarian tumors. Gynecologic oncology 2006; 102(3):429-31.
[18] Wasielewski M, Vasen H, Wijnen J, Hooning M, Dooijes D, Tops C, Klijn JG, Meijers-Heijboer H, Schutte M. CHEK2 1100delC is a susceptibility allele for HNPCC-related colorectal cancer. Clinical cancer research 2008; 14(15):4989-94.
[19] Cybulski C, Wokolorczyk D, Jakubowska A, Huzarski T, Byrski T, Gronwald J, Masojc B, Debniak T, Górski B, Blecharz P, Narod SA, Lubinski J. Risk of Breast Cancer in Women With a CHEK2 Mutation With and Without a Family History of Breast Cancer.J Clin Oncol. 2011 Aug 29. [Epub ahead of print]
[20] Manoukian S et al. Two new CHEK2 germ-line variants detected in breast cancer/sarcoma families negative for BRCA1, BRCA2, and TP53 gene mutations. Breast cancer research and treatment 2011; 130:207-15.
[21] Huijts PE et al. CHEK2*1100delC homozygosity in the Netherlands-prevalence and risk of breast and lung cancer.Eur J Hum Genet. 2013 May 8. doi: 10.1038/ejhg.2013.85. [Epub ahead of print]
[22] Adank MA et al. CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women. Journal of medical genetics 2011; 48:860-3.
[23] Weischer M et al. CHEK2*1100delC and risk of malignant melanoma: Danish and German studies and meta-analysis. The Journal of investigative dermatology 2012; 132:299-303.