ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.470T>C (p.Ile157Thr) (rs17879961)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212410 SCV000149927 likely pathogenic not provided 2018-09-21 criteria provided, single submitter clinical testing This apparently homozygous variant is denoted CHEK2 c.470T>C at the cDNA level, p.Ile157Thr (I157T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). Normal CHEK2 is activated in response to DNA damage, preventing further cell division. The resultant Ile157Thr variant protein demonstrates impairment, with loss of activity with respect to CHEK2-mediated DNA damage response, inability to appropriately bind to checkpoint proteins including p53, and inability to autophosphorylate (Falck 2001, Schwarz 2003, Roeb 2012). In addition, Kilpivaara et al. (2004) suggested the Ile157Thr variant protein may dimerize with normal CHEK2 protein and act in a dominant-negative fashion. Pedigrees of at least two large families displayed incomplete segregation of this variant with breast cancer, not explaining all disease (Roeb 2012). This variant was observed at an allele frequency of 0.5% (1,403/277,192) in large population cohorts, but is more common in particular populations, such as Finland and Poland with population frequencies of up to 5.3% and 4.8%, respectively (Desrichard 2011, Lek 2016). While the variant is likely a founder, it may also represent a hotspot since multiple distinct haplotype backgrounds exist (Kaufman 2009). This variant is located in the Forkhead-associated domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. In sum, Ile157Thr impairs CHEK2 activity while displaying moderate risk, incomplete segregation with disease, and incomplete penetrance. Based on currently available evidence, we consider CHEK2 Ile157Thr to be a likely pathogenic variant. A single variant can sometimes appear to be homozygous if the opposite allele is unable to be amplified or is otherwise undetectable. Therefore, we cannot exclude the possibility that this patient has only one copy of this variant, which could be determined by parental testing. Homozygosity for CHEK2 Ile157Thr has been reported in individuals with breast, colon, and prostate cancer with most authors noting the phenotypes did not appear to differ from heterozygous carriers (Seppala 2003, Kilpivaara 2004, Kilpivaara 2006, Cybulski 2009). Studies suggest the breast cancer risk associated with homozygosity for the truncating variant CHEK2 c.1100delC may be higher than the risk for women with only one copy of the variant (Adank 2011, Huijts 2014), but those data may not be applicable to CHEK2 Ile157Thr homozygosity. Kaczmarek-Rys et al. (2015) identified 3 individuals with papillary thyroid cancer who were homozygous for CHEK2 Ile157Thr and reported a higher odds ratio than for their heterozygous carriers. However, the confidence interval was wide and more data are needed to determine if this association is real. CHEK2 Ile157Thr is associated with an increased risk for certain cancers, including breast, colon, prostate, and others as described below. The majority of studies on CHEK2 Ile157Thr have analyzed heterozygous carriers, and those risks are presented below. The National Comprehensive Cancer Network has management guidelines for individuals with pathogenic variants in CHEK2 (NCCN). Breast Cancer: Case control studies have demonstrated a statistically significant association with breast cancer, with an odds ratio (OR) of approximately 1.5 for sporadic and up to 1.85 for familial cases (Desrichard 2011, Liu 2012, Han 2013). Furthermore, a large meta-analysis suggested a stronger association of this variant with lobular breast cancer compared to controls (OR>4.1) (Liu 2012). Although recent studies have reported a significant association for CHEK2 pathogenic variants with male breast cancer, which was strongest for c.1100delC (OR=3.8-4.5), other data are conflicting, and the association is not significant for Ile157Thr alone (p=0.6) (Ohayon 2004, Neuhausen 2004, Falchetti 2008, Wasielewski 2009, Leedom 2016, Hallamies 2017, Pritzlaff 2017). Colon and Prostate Cancer: CHEK2 Ile157Thr was also observed at a higher frequency in colon cancer cases (OR=1.4-1.67 sporadic or unselected, and OR=1.9-2.1 familial) (Kilpivaara 2006, Suchy 2010, Han 2013). In addition, the variant is associated with familial prostate cancer (OR=2.12-3.8) (Seppala 2003, Cybulski 2004). Although some studies have reported an increased risk for non-familial prostate cancer, results have not been consistent (Seppala 2003, Cybulski 2004, Cybulski 2006, Cybulski 2013). Other Cancers: Associations with other cancers have also been reported for Ile157Thr such as gastric, thyroid, and renal cancers (Cybulski 2004, Teodorczyk 2013, Kaczmarek-Rys 2015, Siolek 2015, Carlo 2018).
Ambry Genetics RCV000116018 SCV000183804 pathogenic Hereditary cancer-predisposing syndrome 2018-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Significant disease association in appropriately sized case-control study(ies),Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification
Invitae RCV000144596 SCV000253984 pathogenic Familial cancer of breast 2019-01-09 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 157 of the CHEK2 protein (p.Ile157Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs17879961, ExAC 2.6%). This variant has been reported in the literature in large meta-analyses involving several thousand cases and controls. Individuals who carried the Ile157Thr variant had a slightly increased risk of breast cancer (OR=1.48-1.58) (PMID: 22799331, 23713947), and colorectal cancer (OR=1.48-1.67) (PMID: 22901170, 23713947). The risk was found to be more pronounced for lobular type breast tumors (OR=4.17) (PMID: 22799331). In addition, smaller case-control studies suggest this variant may also lead to increased risk of additional cancers, including kidney, prostate, thyroid, and gastric cancer (PMID: 15492928, 23296741, 24599715). ClinVar contains an entry for this variant (Variation ID: 5591). Experimental studies find that this missense change reduces the binding of the CHEK2 protein to Cdc25A, BRCA1 and p53 proteins in vitro and may have a dominant-negative effect in cells, although it does not have an effect on CHEK2 protein kinase activity (PMID: 11298456, 11571648, 15239132, 12049740, 22419737). The relationship between these experimental findings and cancer risk is unclear. In summary, this variant is reported to cause an increased risk for cancer. However, since this variant is associated with a much lower risk than other Pathogenic alleles in the CHEK2 gene, it has been classified as Pathogenic (low penetrance).
University of Washington Department of Laboratory Medicine,University of Washington RCV000210131 SCV000266064 likely pathogenic Breast and colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
Color RCV000116018 SCV000292120 pathogenic Hereditary cancer-predisposing syndrome 2014-12-26 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000210131 SCV000296968 likely pathogenic Breast and colorectal cancer, susceptibility to 2018-05-03 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212410 SCV000575329 uncertain significance not provided 2019-04-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000499814 SCV000594119 pathogenic Breast cancer, susceptibility to 2017-06-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212410 SCV000601169 pathogenic not provided 2017-02-17 criteria provided, single submitter clinical testing
Counsyl RCV000144596 SCV000677722 likely pathogenic Familial cancer of breast 2016-03-15 criteria provided, single submitter clinical testing I157T has a reduced penetrance compared to the pathogenic CHEK2 mutation, c.1100delC.
Integrated Genetics/Laboratory Corporation of America RCV000120555 SCV000698803 uncertain significance not specified 2019-04-15 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.470T>C (p.Ile157Thr) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0042 in 253524 control chromosomes in the gnomAD database, including 11 homozygotes. The observed variant frequency is approximately 13.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031). In addition, this variant has been reported in 47/7325 European American women (including 1 homozygote) who are older than age 70 and cancer free (in the FLOSSIES database). These data suggest that the variant is benign polymorphism. However, c.470T>C has been reported in the literature in several individuals affected with Hereditary Breast and Ovarian Cancer. In families with this variant, transmissions of the variant allele and transmissions of the reference allele to affected individuals was reported in addition to unaffected individuals who harbored the variant (Allinen 2001, Dong 2003, Roeb 2012, Bak_2014, Cragun_2014, Stradella_2018). These data indicate that the variant is likely to be associated with disease but also suggests incomplete segregation and incomplete penetrance associated with this variant. Co-occurrences with other pathogenic variants have been reported in CHEK2 as well as in other genes associated with cancer (e.g. BRCA2 c.6468_6469delTC [p.Gln2157fsX18]; NBN c.657_661delACAAA [p.Lys219fsX16]; BRCA1 c.3700_3704delGTAAA [p.Val1234fsX8]; CHEK2 c.444+1G>A; CHEK2 1100delC [p.Thr367fsX15]; CHEK2 c.433C>T [p.Arg145Trp]), providing supporting evidence for a benign role, though in some of these cases the observed phenotype (earlier onset), could also suggest an additive effect (Stradella 2018). Multiple association studies have produced conflicting results, but with an overall consensus for the variant being associated with a moderate increased risk for breast cancer based on a large meta-analysis by Liu 2012 that included a total of fifteen case-control studies (19,621 cases and 27,001 controls), showing a significant association for unselected breast cancer (OR = 1.48, 95% CI = 1.31-1.66, P < 0.0001), familial breast cancer (OR = 1.48, 95% CI = 1.16-1.89, P < 0.0001), early-onset breast cancer (OR = 1.47, 95% CI = 1.29-1.66, P < 0.0001), and especially for lobular type breast tumors (OR = 4.17, 95% CI = 2.89-6.03, P < 0.0001). However, other association studies do not provide a clear indication for the variant being a risk factor for other cancers and a recent large study found no statistically significant difference in overall or breast cancer-specific survival between carriers of this variant and non-carriers, suggesting this could be a low risk factor/reduced penetrance allele (Muranen 2016, Leedom 2016). Multiple functional studies reported experimental evidence evaluating an impact on protein function, demonstrating retained kinase activity (Chrisanthar 2008, Lee 2001), decreased interaction with p53 and BRCA1 (Falck 2001, Li 2002) and impaired CHEK2 oligomerization with reduced autophosphorylation (Schwarz 2003). Fifteen other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Multiple laboratories reported the variant with conflicting assessments: uncertain significance (2), likely pathogenic (7), and pathogenic (6) while acknolwedging the low penetrance and risk association of this variant. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic, due to the probability of this variant for being a possible moderate risk factor for HBOC.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626718 SCV000747421 uncertain significance Gastrointestinal carcinoma; Adrenocortical carcinoma 2017-01-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212410 SCV000806880 likely pathogenic not provided 2016-09-14 criteria provided, single submitter clinical testing
GeneKor MSA RCV000116018 SCV000821722 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000144596 SCV000839491 likely pathogenic Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000144596 SCV000839939 pathogenic Familial cancer of breast 2017-06-02 criteria provided, single submitter clinical testing This c.470T>C (p.Ile157Thr) variant in the CHEK2 gene has been reported to be associated with cancer susceptibility, including significant association with increased risk of breast and colon cancer in large meta-analysis studies [odds ratios ~1.5, PMID: 22901170, 22799331, 23713947]. Co-segregation in families is variable: while families have been reported with complete penetrance, others show incomplete penetrance [PMID 22419737]. In vitro and in vivo studies have shown that the mutant allele does not affect the kinase activity of the protein [PMID 11719428] but does affect the dimerization of the protein in a dominant negative manner, resulting in the lack of autophosphosphorylation [PMID 12805407]. The mutant protein also impaired the binding of CHEK2 to check point proteins including CDC25A in response to DNA damage [PMID 11298456]. This variant was reported in 497 heterozygous and 6 homozygous individuals in the ExAC population database ( Isoleucine at amino acid position 157 of the CHEK2 protein is conserved in mammals. While not validated for clinical use, computer-based algorithms (SIFT and Polyphen-2) predict this p.Ile157Thr change to be deleterious. It is thus classified as a pathogenic variant.
OMIM RCV000005936 SCV000026118 pathogenic Li-Fraumeni syndrome 2 2006-11-01 no assertion criteria provided literature only
OMIM RCV000005937 SCV000026119 risk factor Colorectal cancer, susceptibility to 2006-11-01 no assertion criteria provided literature only
OMIM RCV000005938 SCV000026120 risk factor Cancer of multiple types, susceptibility to 2006-11-01 no assertion criteria provided literature only
OMIM RCV000005939 SCV000026121 risk factor Prostate cancer, susceptibility to 2006-11-01 no assertion criteria provided literature only
ITMI RCV000120555 SCV000084709 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144596 SCV000189923 likely pathogenic Familial cancer of breast 2014-07-24 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000212410 SCV000691835 pathogenic not provided no assertion criteria provided clinical testing
True Health Diagnostics RCV000116018 SCV000788004 pathogenic Hereditary cancer-predisposing syndrome 2017-11-16 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000844971 SCV000986797 not provided Breast cancer, susceptibility to; COLON CANCER, SUSCEPTIBILITY TO no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 05/09/2018 by GTR ID 61756. 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.

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