Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing


      • Some, but not all, CHEK2 missense PVs demonstrate lower cancer prevalence.
      • Biallelic CHEK2 PVs may not be associated with a more severe phenotype.
      • CHEK2 heterozygotes often also carry PVs in other cancer risk genes.



      Although CHEK2 is a well-established cancer gene, questions remain including whether risks vary substantially between different variants and whether biallelic carriers have higher risks than heterozygotes. We report on a cohort of individuals with CHEK2 pathogenic and likely pathogenic variants (collectively, PV) in order to better characterize this gene.


      We retrospectively queried samples submitted for multi-gene hereditary cancer testing to identify individuals with CHEK2 PVs and assessed differences in phenotypes among various genotypes.


      CHEK2 PVs were identified in 2508 individuals, including 32 individuals with biallelic CHEK2 PVs. Breast (female, 59.9% and male, 11.8%), prostate (20.1%), and colorectal (3.5%), were among the most frequently reported cancers. Select missense PVs showed similar cancer prevalence to truncating PVs while some others showed lower prevalence. No significant differences were observed between biallelic carriers and heterozygotes.


      Our data support that some, but not all, CHEK2 missense PVs demonstrate lower cancer prevalence; further studies are needed to continue characterizing possible variant specific risks. In addition, biallelic CHEK2 PVs do not appear to be associated with a more severe phenotype than single CHEK2 PVs. Furthermore, co-occurrences with PVs in other cancer risk genes are common among CHEK2 heterozygotes and often warrant additional management.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Cancer Genetics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Bell D.W.
        • Varley J.M.
        • Szydlo T.E.
        • et al.
        Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.
        Science. 1999; 286: 2528-2531
        • Ruijs M.W.G.
        • Broeks A.
        • Menko F.H.
        • et al.
        The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype.
        Hered Cancer Clin Pract. 2009; 7: 4
        • Evans D.G.
        • Birch J.M.
        • Narod S.A
        Is CHEK2 a cause of the Li-Fraumeni syndrome.
        J Med Genet. 2008; 45: 63-64
        • Desrichard A.
        • Bidet Y.
        • Uhrhammer N.
        • Bignon Y.-.J
        CHEK2 contribution to hereditary breast cancer in non-BRCA families.
        Breast Cancer Res. 2011; 13: R119
        • Couch F.J.
        • Shimelis H.
        • Hu C.
        • et al.
        Associations between cancer predisposition testing panel genes and breast cancer.
        JAMA Oncol. 2017; 3: 1190-1196
        • Girard E.
        • Eon-Marchais S.
        • Olaso R.
        • et al.
        Familial breast cancer and DNA repair genes: insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.
        Int J Cancer. 2019; 144: 1962-1974
        • Hallamies S.
        • Pelttari L.M.
        • Poikonen-Saksela P.
        • et al.
        CHEK2 c.1100delC mutation is associated with an increased risk for male breast cancer in Finnish patient population.
        BMC Cancer. 2017; 17: 620
        • Pritzlaff M.
        • Summerour P.
        • McFarland R.
        • et al.
        Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results.
        Breast Cancer Res Treat. 2017; 161: 575-586
        • Kleiblova P.
        • Stolarova L.
        • Krizova K.
        • et al.
        Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer.
        Int J Cancer. 2019; 145: 1782-1797
        • Leedom T.P.
        • LaDuca H.
        • McFarland R.
        • Li S.
        • Dolinsky J.S.
        • Chao E.C
        Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers.
        Cancer Genet. 2016; 209: 403-407
        • Ohayon T.
        • Gal I.
        • Baruch R.G.
        • Szabo C.
        • Friedman E
        CHEK2×1100delC and male breast cancer risk in Israel.
        Int J Cancer. 2004; 108: 479-480
        • Rizzolo P.
        • Zelli V.
        • Silvestri V.
        • et al.
        Insight into genetic susceptibility to male breast cancer by multigene panel testing: results from a multicenter study in Italy.
        Int J Cancer. 2019; 145: 390-400
        • Cybulski C.
        • Górski B.
        • Huzarski T.
        • et al.
        CHEK2 is a multiorgan cancer susceptibility gene.
        Am J Hum Genet. 2004; 75: 1131-1135
        • Cybulski C.
        • Wokołorczyk D.
        • Kluźniak W.
        • et al.
        An inherited NBN mutation is associated with poor prognosis prostate cancer.
        Br J Cancer. 2013; 108: 461-468
        • Hale V.
        • Weischer M.
        • Park J.Y
        CHEK2 (∗) 1100delC Mutation and Risk of Prostate Cancer.
        Prostate Cancer. 2014; 2014294575
        • Kilpivaara O.
        • Alhopuro P.
        • Vahteristo P.
        • Aaltonen L.A.
        • Nevanlinna H
        CHEK2 I157T associates with familial and sporadic colorectal cancer.
        J Med Genet. 2006; 43: e34
        • Suchy J.
        • Cybulski C.
        • Wokołorczyk D.
        • et al.
        CHEK2 mutations and HNPCC-related colorectal cancer.
        Int J Cancer. 2010; 126: 3005-3009
        • Seppälä E.H.
        • Ikonen T.
        • Mononen N.
        • et al.
        CHEK2 variants associate with hereditary prostate cancer.
        Br J Cancer. 2003; 89: 1966-1970
        • Ma X.
        • Zhang B.
        • Zheng W
        Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence.
        Gut. 2014; 63: 326-336
        • Teodorczyk U.
        • Cybulski C.
        • Wokołorczyk D.
        • et al.
        The risk of gastric cancer in carriers of CHEK2 mutations.
        Fam Cancer. 2013; 12: 473-478
        • Carlo M.I.
        • Mukherjee S.
        • Mandelker D.
        • et al.
        Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma.
        JAMA Oncol. 2018; 4: 1228-1235
        • Siołek M.
        • Cybulski C.
        • Gąsior-Perczak D.
        • et al.
        CHEK2 mutations and the risk of papillary thyroid cancer.
        Int J Cancer. 2015; 137: 548-552
        • Näslund-Koch C.
        • Nordestgaard B.G.
        • Bojesen S.E
        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
        • Adank M.A.
        • Jonker M.A.
        • Kluijt I.
        • et al.
        CHEK2×1100delC homozygosity is associated with a high breast cancer risk in women.
        J Med Genet. 2011; 48: 860-863
        • Huijts P.E.A.
        • Hollestelle A.
        • Balliu B.
        • et al.
        CHEK2×1100delC homozygosity in the Netherlands–prevalence and risk of breast and lung cancer.
        Eur J Hum Genet. 2014; 22: 46-51
        • Cybulski C.
        • Górski B.
        • Huzarski T.
        • et al.
        Effect of CHEK2 missense variant I157T on the risk of breast cancer in carriers of other CHEK2 or BRCA1 mutations.
        J Med Genet. 2009; 46: 132-135
        • Rainville I.
        • Hatcher S.
        • Rosenthal E.
        • et al.
        High risk of breast cancer in women with biallelic pathogenic variants in CHEK2.
        Breast Cancer Res Treat. January 2020;
        • Kaczmarek-Ryś M.
        • Ziemnicka K.
        • Hryhorowicz S.T.
        • et al.
        The c.470 T > C CHEK2 missense variant increases the risk of differentiated thyroid carcinoma in the Great Poland population.
        Hered Cancer Clin Pract. 2015; 13: 8
        • Offit K.
        • Garber J.E.
        Time to check CHEK2 in families with breast cancer.
        J Clin Oncol. 2008; 26: 519-520
      1. NCCN Guidelines. Genetic/Familial High-Risk Assessment: breast and Ovarian (Version 3.2019). Accessed2019.

      2. NCCN Guidelines. Genetic/Familial High-Risk Assessment: breast and Ovarian (Version 1.2020). Accessed2019.

        • Roberts M.E.
        • Jackson S.A.
        • Susswein L.R.
        • et al.
        MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer.
        Genet Med. 2018;
        • Richards S.
        • Aziz N.
        • Bale S.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
        Genet Med. 2015; 17: 405-424
        • Norquist B.M.
        • Harrell M.I.
        • Brady M.F.
        • et al.
        Inherited Mutations in Women With Ovarian Carcinoma.
        JAMA Oncol. 2016; 2: 482-490
        • Southey M.C.
        • Goldgar D.E.
        • Winqvist R.
        • et al.
        PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.
        J Med Genet. 2016; 53: 800-811
        • Decker B.
        • Allen J.
        • Luccarini C.
        • et al.
        Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
        J Med Genet. 2017; 54: 732-741
        • Shaag A.
        • Walsh T.
        • Renbaum P.
        • et al.
        Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population.
        Hum Mol Genet. 2005; 14: 555-563
        • Balmaña J.
        • Digiovanni L.
        • Gaddam P.
        • et al.
        Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing.
        J Clin Oncol. 2016; 34: 4071-4078
        • Tung N.
        • Domchek S.M.
        • Stadler Z.
        • et al.
        Counselling framework for moderate-penetrance cancer-susceptibility mutations.
        Nat Rev Clin Oncol. 2016; 13: 581-588
        • Cai Z.
        • Chehab N.H.
        • Pavletich N.P
        Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase.
        Mol Cell. 2009; 35: 818-829
        • Roeb W.
        • Higgins J.
        • King M.-.C
        Response to DNA damage of CHEK2 missense mutations in familial breast cancer.
        Hum Mol Genet. 2012; 21: 2738-2744