ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1100del (p.Thr367fs) (rs555607708)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 29
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212447 SCV000149889 pathogenic not provided 2018-08-28 criteria provided, single submitter clinical testing This pathogenic variant is denoted CHEK2 c.1100delC at the cDNA level and p.Thr367MetfsX15 (T367MfsX15) at the protein level. The normal sequence, with the base that is deleted in brackets, is ATTA[delC]TGAT. The deletion causes a frameshift, which changes a Threonine to a Methionine at codon 367 and creates a premature stop codon at position 15 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. In vitro functional analyses have found that CHEK2 c.1100delC results in loss of kinase activity and the inability to phosphorylate Cdc25C, supportive of a pathogenic effect (Lee 2001, Wu 2001). Although present in approximately 0.5 - 1% of healthy European individuals (Meijers-Heijboer 2002, Neuhausen 2004, Wasielewski 2009, Schmidt 2016), based on functional studies and the case-control data summarized below, CHEK2 c.1100delC is considered pathogenic. CHEK2 c.1100delC is associated with an increased risk for certain cancers, including breast, colon, prostate, and others as described below. The National Comprehensive Cancer Network has management guidelines for individuals with pathogenic variants in CHEK2 (NCCN). Breast Cancer: CHEK2 c.1100delC is considered a breast cancer susceptibility allele in Western Populations by The CHEK2 Breast Cancer Case-Control Consortium and is observed at higher frequencies among breast cancer cases, with an odds ratio (OR) of approximately 2.3-3.3 in sporadic or unselected cases, and 3.1-4.2 in familial cases, depending on strength of family history (The CHEK2 Breast Cancer Consortium 2004, Desrichard 2011, Schmidt 2016, Couch 2017, Decker 2017). Compared with breast cancer patients without CHEK2 c.1100delC, women who carried the pathogenic variant had higher rates of a second breast cancer, particularly if the first was estrogen-receptor positive (Weischer 2012, Muranen 2016). Although previous studies have not observed a statistically significant association with male breast cancer (Syrjakoski 2003, Ohayon 2004, Neuhausen 2004, Falchetti 2008), recent reports, including a large meta-analysis, indicate a statistically higher incidence of breast cancer in men with c.1100delC (Hallamies 2017, Pritzlaff 2017, Liang 2018). Colon and Prostate Cancer: Earlier studies did not show a statistically significant association for CHEK2 c.1100delC with colorectal cancer (CRC) (Kilpivaara 2003, Djureinovic 2006, Kleibl 2008). However, data from recent large meta-analyses may suggest an association supported by a modestly elevated OR (approximately 1.8) in unselected CRC cases (Ma 2014, Katona 2017). CHEK2 c.1100delC has previously been associated with familial prostate cancer with varying odds ratios and wide confidence intervals (Seppala 2003, Cybulski 2006). A meta-analysis of five studies with independent data reported an increased risk for prostate cancer in men with CHEK2 c.1100delC in both unselected (OR=1.98) and familial (OR=3.39) cases (Hale 2014). Additionally, the relative risk (RR=3.1; p=0.002) of CHEK2 alterations, especially truncating variants, in unselected patients with metastatic prostate cancer was shown to be elevated (Pritchard 2016). Other Cancers: Case-control studies have found significant associations for CHEK2 c.1100delC and other truncating variants with papillary thyroid cancer, gastric cancer, and renal cancer (Teodorczyk 2013, Siolek 2015, Naslund-Koch 2016, Carlo 2018).
Invitae RCV000123265 SCV000166572 pathogenic Familial cancer of breast 2019-01-11 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 11 of the CHEK2 mRNA (c.1100delC), causing a frameshift at codon 367. This creates a premature translational stop signal (p.Thr367Metfs*15) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic. This particular variant has been well described in the literature. In a large meta-analysis comprising 16 studies including 26,488 affected individuals and 27,402 controls, women heterozygous for this variant have a relative risk for familial breast cancer of 4.8 (95% CI, 3.3-7.2). The cumulative risk at age 70 years is 37% (95% CI, 26%-56%), compared to 7.8% for the average Caucasian woman in the general population (PMID: 18172190). Although one study has reported that the c.1100delC variant confers an approximate 10-fold increased risk of male breast cancer (PMID: 11967536), the results have yet to be confirmed in further studies (PMID: 14648717, 14648718, 14648719, 15488637). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000115980 SCV000187220 pathogenic Hereditary cancer-predisposing syndrome 2017-09-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Other strong data supporting pathogenic classification,Significant disease association in appropriately sized case-control study(ies)
University of Washington Department of Laboratory Medicine,University of Washington RCV000210137 SCV000266067 pathogenic Breast and colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
Color RCV000115980 SCV000292118 pathogenic Hereditary cancer-predisposing syndrome 2015-02-17 criteria provided, single submitter clinical testing
Counsyl RCV000123265 SCV000488123 pathogenic Familial cancer of breast 2016-01-20 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000413386 SCV000492465 pathogenic Neoplasm of the breast criteria provided, single submitter research
Genetic Services Laboratory, University of Chicago RCV000500025 SCV000594116 pathogenic Breast cancer, susceptibility to 2016-08-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212447 SCV000601142 pathogenic not provided 2016-07-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212447 SCV000603087 pathogenic not provided 2018-03-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515188 SCV000611258 pathogenic Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2017-05-18 criteria provided, single submitter clinical testing
Laboratory of Molecular Neuropathology,The University of Texas Health Science Center at Houston RCV000591014 SCV000692550 uncertain significance Astrocytoma criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587467 SCV000698761 pathogenic Li-Fraumeni syndrome 2019-07-25 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1100delC (p.Thr367MetfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.002 in 248982 control chromosomes (gnomAD). Although this variant was found at a relatively high frequency in controls, this is a well-known founder mutation that is known to be relatively frequent in European populations. c.1100delC has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and also as risk factor for several cancer types (breast, ovarian, prostate, colon, etc.). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this variant leads to loss of damage response and kinase activity (Lee_2001, Roeb_2012). Eighteen other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000615743 SCV000711416 pathogenic CHEK2-Related Cancer Susceptibility 2015-03-10 criteria provided, single submitter clinical testing The c.1100delC (p.Thr367fs) variant in CHEK2 has been associated with increased risk for several types of cancer, including breast, colorectal, and prostate. Me ta-analyses have reported an odds ratio of 2-4 for developing breast, colorectal , or prostate cancer, and a possibly smaller increased risk of malignant melanom a (Weischer 2008, Xiang 2011, Weischer 2012, Yang 2012, Wang 2015). In addition, animal models in mice have shown that this variant causes increased tumor forma tion in multiple cancer sites (Bahassi 2009). This variant has also been reporte d by other clinical laboratories in ClinVar (Variation ID 128042). Of note, this variant has been identified in 0.3% (319/125272) of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 35705950). Therefore, this variant is not expected to cause highly penetrant Men delian disease. In summary, the c.1100delC (p.Thr367fs) variant is an establishe d risk factor for breast, colorectal, and prostate cancers.
PreventionGenetics,PreventionGenetics RCV000212447 SCV000806862 pathogenic not provided 2016-05-31 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115980 SCV000821726 pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000123265 SCV000839467 pathogenic Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735378 SCV000854533 pathogenic Colitis; Inflammation of the large intestine; Hematochezia; Thrombocytopenia criteria provided, single submitter clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761109 SCV000891024 pathogenic Diffuse intrinsic pontine glioma 2016-10-05 criteria provided, single submitter clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761147 SCV000891063 pathogenic B Lymphoblastic Leukemia/Lymphoma, Not Otherwise Specified 2016-11-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000615743 SCV000915968 pathogenic CHEK2-Related Cancer Susceptibility 2017-04-27 criteria provided, single submitter clinical testing The CHEK2 c.1100delC (p.Thr367MetfsTer15) variant is a common variant in individuals of European origin and has been investigated in multiple studies in various cancer types. A meta-analysis of ten case-control studies, including 10,860 breast cancer cases and 9,065 controls by the CHEK2 Breast Cancer Case-Control Consortium (2004) found a statistically significant association between carrying the p.Thr367MetfsTer15 variant and increase in risk of breast cancer (OR=2.34). The association of the p.Thr367MetfsTer15 variant and increased risk of breast cancer was also supported by Bernstein et al. (2006) (OR=6.65) and Weischer et al. (2007) (OR=3.2). Weischer et al. (2007) also found an association between the variant and increased risk of prostate cancer (OR=2.3) and colorectal cancer (OR=1.6). Weischer et al. (2012) found an association of the p.Thr367MetfsTer15 variant and increased risk of malignant melanoma in both a case-control study (OR=1.79) and a meta-analysis (OR=1.81). The p.Thr367MetfsTer15 variant has also been identified in patients with Li-Fraumeni syndrome (Bell et al. 1999), colon, kidney, prostate, and thyroid cancers (Cybulski et al. 2004), ovarian cancer (Walsh et al. 2011), and uterine cancer (Pennington et al. 2013), though the associated risks for these cancers due to this variant are unclear at this time. Studies by Lee et al. (2001) found a lack of kinase activity and evidence of loss of heterozygosity in a tumor sample from a patient carrying the germline p.Thr367MetfsTer15 variant. The highest allele frequency reported in the 1000 Genomes database is 0.0202 in the Finnish population. Although an association with the p.Thr367MetfsTer15 variant and susceptibility to different cancers is widely reported, the increase in risk is low to moderate. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Academic Department of Medical Genetics, University of Cambridge RCV000115980 SCV000992228 pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Pathway Genomics RCV000123265 SCV000189922 pathogenic Familial cancer of breast 2014-07-24 no assertion criteria provided clinical testing
Genome Sciences Centre,British Columbia Cancer Agency RCV000488416 SCV000574565 pathogenic Neoplasm of the breast; Leiomyosarcoma no assertion criteria provided clinical testing Positive family history of early breast cancer (niece diagnosed at age 35). Whole genome sequencing (blood and tumor) and whole transcriptome sequencing (tumor) also revealed the germline CHEK2:c.1100delC pathogenic variant, which is considered a moderate penetrance allele for breast cancer.
GenomeConnect, ClinGen RCV000509136 SCV000607207 not provided Hereditary cancer no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000212447 SCV000691834 pathogenic not provided no assertion criteria provided clinical testing
True Health Diagnostics RCV000115980 SCV000787999 pathogenic Hereditary cancer-predisposing syndrome 2017-11-14 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000212447 SCV000840164 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785429 SCV000924001 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.