ClinVar Miner

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

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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212410 SCV000149927 likely pathogenic not provided 2019-09-30 criteria provided, single submitter clinical testing Case control studies suggest this variant is associated with several types of cancer, including breast, colon, prostate, gastric, renal, and thyroid cancers, though some odds ratios are only modestly elevated (Seppala 2003; Cybulski 2004; Kilpivaara 2006; Suchy 2010; Desrichard 2011; Liu 2012; Roeb 2012; Han 2013; Teodorczyk 2013; Kaczmarek-Rys 2015; Siolek 2015; Carlo 2018) Published functional studies demonstrate a damaging effect with respect to autophosphorylation, binding of downstream targets, and DNA damage response, and may exhibit a dominant-negative effect, while studies assessing kinase activity have varied results (Falck 2001a; Falck 2001b; Lee 2001; Wu 2001; Li 2002; Schwarz 2003; Kilpivaara 2004; Roeb 2012) Observed in 0.5% (1,403/277,192) of global alleles in large population cohorts, and is considered a founder variant with a frequency of up to 5.3% and 4.8%, respectively, in Finnish and Polish individuals (Desrichard 2011; Lek 2016) Located in a critical functional domain: forkhead-associated (FHA) 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
Ambry Genetics RCV000116018 SCV000183804 pathogenic Hereditary cancer-predisposing syndrome 2018-06-20 criteria provided, single submitter clinical testing 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 2020-01-14 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 2020-02-09 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 2020-06-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000499814 SCV000594119 risk factor Breast cancer, susceptibility to 2019-12-06 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 2020-01-01 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 physiochemical difference between isoleucine and threonine.This variant is present in population databases (rs17879961, 2.6%) and has been reported in the literature. ClinVar contains entries for this variant (RC000116018, RC000144596).In large meta-analyses involving several thousand cases and controls, patients who carried this 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 breast tumors (OR=4.17) (PMID: 22799331).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).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 the 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 Likely Pathogenic (low penetrance).
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 (http://exac.broadinstitute.org/variant/22-29121087-A-G). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000120555 SCV001159433 pathogenic not specified 2019-01-02 criteria provided, single submitter clinical testing The CHEK2 c.470T>C; p.Ile157Thr variant (rs17879961) is reported in the medical literature in large case-controlled meta-analyses as associated with a slightly increased risk of breast cancer, colon cancer, kidney cancer, prostate cancer, thyroid cancer, and gastric cancer (Cybulski 2004, Han 2013, Teodorczyk 2013). In vitro assays suggest the variant protein has wildtype kinase activity but fails to interact with normal binding partners (Falck 2001, Li 2002, Wu 2001). The p.Ile157Thr variant is listed as pathogenic/likely pathogenic by numerous laboratories in ClinVar (Variation ID: 5591), though it is found in the general population with an overall allele frequency of 0.5% (1391/282816 alleles) in the Genome Aggregation Database. Due to the small but statistically significant increased risk of cancer, this variant is classified as a low penetrance pathogenic variant. References: Cybulski C et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004 Dec;75(6):1131-5. Falck J et al. Functional impact of concomitant versus alternative defects in the Chk2-p53 tumour suppressor pathway. Oncogene. 2001 Sep 6;20(39):5503-10. Han FF et al. The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a meta-analysis. DNA Cell Biol. 2013 Jun;32(6):329-35. Li J et al. Structural and functional versatility of the FHA domain in DNA-damage signaling by the tumor suppressor kinase Chk2. Mol Cell. 2002 May;9(5):1045-54. Teodorczyk U et al. The risk of gastric cancer in carriers of CHEK2 mutations. Fam Cancer. 2013 Sep;12(3):473-8. Wu X et al. Characterization of tumor-associated Chk2 mutations. J Biol Chem. 2001 Jan 26;276(4):2971-4.
Institute of Human Genetics, University of Leipzig Medical Center RCV000144596 SCV001429096 uncertain significance Familial cancer of breast 2018-02-26 criteria provided, single submitter clinical testing
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.
Center of Medical Genetics and Primary Health Care RCV000144596 SCV000987254 likely pathogenic Familial cancer of breast 2020-04-08 no assertion criteria provided research ACMG Guidelines 2015 criteria The CHEK2 variant p.Ile157Thr was observed in the kinase domain in a tight region between amino acid 407-499 and in a mutation hotspot of 13 pathogenic variants (PM1 Pathogenic Moderate). 4 functional studies (PMID: 12049740, 15239132, 11298456, & 11571648) confirmed the likely pathogenic effect of this variant (PS3 Pathogenic Strong). An alternative variant (chr22:29121087 A>C (Ile157Ser)) at the same amino acid residue is classified as likely pathogenic (PM5 Pathogenic Moderate). Meantime, majority of missense variants detected in CHEK2 are pathogenic and known cause of disease (PP2 Pathogenic Supporting). The homozygous allele count in GnomAD exomes is 11 which is greater the threshold 3 for dominant and recessive gene CHEK2 (BS2 Benign Strong). In our study the variant p.Ile157Thr was found in a 46-year-old female with family history of cancer. In summary, based on the evidence and given the previous reports of the variant in association with increased risk of breast cancer, we classified this variant as a Likely Pathogenic.

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