ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met) (rs142763740)

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Total submissions: 30
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212465 SCV000149910 likely pathogenic not provided 2019-01-07 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1427C>T at the cDNA level, p.Thr476Met (T476M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been reported in individuals with a personal and/or family history of breast, pancreatic, or prostate cancer (Desrichard 2011, Le Calvez-Kelm 2011, Hu 2015, Leedom 2016, Pritzlaff 2016, Shirts 2016, Frey 2017, Isaacsson Velho 2018, Schubert 2018, Wu 2018). This variant was shown in an in vitro study to abolish kinase activity, and was shown in an in vivo study to impair CHEK2-mediated response to DNA damage (Desrichard 2011, Roeb 2012). A different nucleotide change (CHEK2 c.1427C>A) resulting in the same amino acid substitution was identified in a patient with a clinical diagnosis of Li-Fraumeni syndrome (Sadri 2014). Although this variant was observed in large population cohorts, population data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). CHEK2 Thr476Met is located in the protein kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider CHEK2 Thr476Met to be a likely pathogenic variant.
Ambry Genetics RCV000116001 SCV000186804 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-04 criteria provided, single submitter clinical testing The p.T476M variant (also known as c.1427C>T), located in coding exon 12 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1427. The threonine at codon 476 is replaced by methionine, an amino acid with similar properties. This alteration has been detected in multiple individuals with a personal and/or family history of breast cancer (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6; Angelova SG et al. Neoplasma. 2012;59:622-30; Susswein LR et al. Genet. Med. 2016 08;18:823-32; Frey MK et al. Gynecol. Oncol. 2017 07;146:123-128). This variant has also been reported in a patient clinically considered to have Li-Fraumeni syndrome (Sadri N et al. Virchows Arch. 2014 Apr;464:505-9). This alteration is located in the kinase domain of CHK2 and has been shown to be associated with complete loss of kinase and DNA damage response activities (Desrichard A et al. Breast Cancer Res. 2011 Nov;13:R119; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000198554 SCV000254925 uncertain significance Familial cancer of breast 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 476 of the CHEK2 protein (p.Thr476Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs142763740, ExAC 0.07%). This variant has been reported in individuals affected with breast cancer (PMID: 21244692, 31050813), endometrial cancer (PMID: 27443514), ovarian cancer (PMID: 31050813), colorectal cancer (PMID: 28944238), prostate cancer (PMID: 29368341, 29520813), in a male with breast and colon cancer (PMID: 28008555), and in healthy control individuals (PMID: 31050813). The results of a history weighting algorithm suggest that this variant does not show an association with breast cancer risk as expected for known pathogenic CHEK2 variants (external communication). ClinVar contains an entry for this variant (Variation ID: 128060). This variant has been reported to have conflicting or insufficient data to determine the effect on CHEK2 protein function (PMID: 22114986, 22419737, 31050813, 30851065). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV000210077 SCV000266166 uncertain significance Breast and colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000259876 SCV000437713 uncertain significance Colorectal cancer 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000317389 SCV000437714 likely pathogenic Breast neoplasm 2016-06-14 criteria provided, single submitter clinical testing Across three studies, the c.1427C>T (p.Thr476Met), was reported in five of 1,955 breast cancer patients (Le Calvez-Kelm et al. 2011; Desrichard et al. 2011; Angelova et al. 2012). The variant was absent from a total of 1,622 controls, but is reported at a frequency of 0.00068 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Desrichard et al. (2011) developed an in vitro kinase activity assay to assess the activity of missense variants in CHEK2. In this assay the p.Thr476Met variant demonstrated no kinase activity and was similar to a known non-functional kinase variant of CHEK2. In addition, Roeb et al. (2012) developed a yeast-based in-vivo functional assay to assess the effect of CHEK2 variants on the repair of DNA damage. Cells with wild-type CHEK2 repaired the DNA damage while cells with a known non-functional variant of CHEK2 did not. The p.Thr476Met variant was shown to have loss of function by this DNA damage response assay. Based on the evidence, the p.Thr476Met variant is classified as likely pathogenic for breast cancer.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000116001 SCV000576430 likely pathogenic Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000499890 SCV000594113 likely pathogenic not specified 2019-07-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212465 SCV000601155 likely pathogenic not provided 2020-04-23 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Predicted to have a damaging effect on the protein. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Occurs in a single case with an alternate molecular basis for disease. Assessment of experimental evidence suggests this variant results in abnormal protein function.
GeneID Lab - Advanced Molecular Diagnostics RCV000116001 SCV000680448 likely pathogenic Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000116001 SCV000689655 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-01 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 476 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have demonstrated inconsistent results. This variant has been shown to impair CHEK2 kinase activity in vitro using bacteria produced protein (PMID: 22114986, 31050813), but displayed normal activity using a human cell kinase assay (PMID: 31050813). DNA damage repair assays in yeast have shown intermediate to complete defects (PMID: 22419737, 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 15095295, 21244692, 22114986, 22862163, 24595525, 25186627, 26681312, 28008555, 28495237 30426508, 32658311, 32805687, 32906215, 33030641), prostate cancer (PMID: 29368341, 29520813), colorectal cancer (PMID: 28008555, 28135145, 28944238, 32658311), pancreatic cancer (PMID: 26483394, 26845104 29945567), endometrial cancer (PMID: 27443514), as well as in individuals unaffected with cancer (PMID: 32658311). A history weighting algorithm score was inconsistent with that expected for CHEK2 pathogenic mutations (Mundt, et al. poster #154, ACMG 2017). This variant has been identified in 83/265178 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000198554 SCV000778585 uncertain significance Familial cancer of breast 2018-04-16 criteria provided, single submitter research
Counsyl RCV000198554 SCV000785095 uncertain significance Familial cancer of breast 2017-10-06 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212465 SCV000806869 likely pathogenic not provided 2016-09-30 criteria provided, single submitter clinical testing
GeneKor MSA RCV000116001 SCV000821724 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This variation detected results in the substitution of the amino acid Threonine with Methionine at codon 476 of the CHEK2 protein. The threonine residue is highly conserved among species in the Protein kinase domain of the protein and there is physiochemical difference between threonine and methionine (Grantham Score 81). This variant has been described in the international literature in individuals affected with breast and endometrial cancers (PMID: 21244692, PMID: 27443514).This variant is present in mutation databases at a low frequency (rs142763740, ExAC 0.07%). The mutation database ClinVar contains entries for this variant (Variation ID: 128060). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein, a prediction supported also by experimental studies. (PMID: 22114986, PMID: 22419737).
Mendelics RCV000198554 SCV000839455 likely pathogenic Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778653 SCV000914986 likely pathogenic CHEK2-Related Cancer Susceptibility 2017-04-27 criteria provided, single submitter clinical testing The CHEK2 c.1427C>T (p.Thr476Met) missense variant, also referred to as c.1556C>T (p.Thr519Met), was reported in five of 1,955 breast cancer patients (Le Calvez-Kelm et al. 2011; Desrichard et al. 2011; Angelova et al. 2012). The variant was absent from a total of 1,622 controls, but is reported at a frequency of 0.00068 in the European (non-Finnish) population of the Exome Aggregation Consortium. Desrichard et al. (2011) developed an in vitro kinase activity assay to assess the activity of missense variants in CHEK2. In this assay the p.Thr476Met variant demonstrated no kinase activity and was similar to a known non-functional kinase variant of CHEK2. In addition, Roeb et al. (2012) developed a yeast-based in-vivo functional assay to assess the effect of CHEK2 variants on the repair of DNA damage. Cells with wild type CHEK2 repaired the DNA damage while cells with a known non-functional variant of CHEK2 did not. The p.Thr476Met variant was shown to have loss of function by this DNA damage response assay. Based on the evidence, the p.Thr476Met variant is classified as pathogenic for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212465 SCV001249408 likely pathogenic not provided 2021-04-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000499890 SCV001339088 uncertain significance not specified 2021-07-26 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1427C>T (p.Thr476Met) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 238040 control chromosomes. The observed variant frequency is approximately the same as the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031), strongly suggesting that the variant is benign. Additionally, this variant has been observed in 8 individuals who are reportedly cancer free at age 70 in the FLOSSIES database. In addition, co-occurrences with other pathogenic variants have been observed at our laboratory (BRCA2 c.8677C>T, p.Gln2893*; PMS2 c.2444C>T, p.Ser815Leu), providing additional supporting evidence for a benign role. c.1427C>T has been reported in the literature in individuals affected with Breast, Ovarian, Colorectal, and Pancreatic cancers (example, Le Calvez-Kelm_2011, Angelova_2012, Susswein_2015, Hu_2016, Schuber_2019, Henn_2019, Bertelsen_2019, Lerner-Ellis_2019). For some of these cases multigenic panel screening was performed, however, in most cases, the co-occurrence information was not provided and segregation studies were not performed. In addition, Leedom_2016 reported similar frequencies for the variant in their affected (at risk) population of European descent (0.07%; 46/62392 chromosomes tested). This variant was identified in an individual who tested positive for a large deletion encompassing exon 9-15 of CHEK2 in trans in an internal specimen.These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in disruption of CHEK2 kinase activity in vitro and impairs DNA damage response in a yeast assay (example, Desrichard_2011; Roeb_2012, Delimitsou_2019), suggesting a deleterious outcome or at least a possible modifying role of the variant in carcinogenesis. Multiple clinical diagnostic laboratories and other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance until more definitive data becomes available.
Institute of Human Genetics, University of Leipzig Medical Center RCV000198554 SCV001429101 uncertain significance Familial cancer of breast 2018-02-23 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000212465 SCV001447152 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000116001 SCV001448806 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-12 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000212465 SCV001449986 likely pathogenic not provided 2020-01-21 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000198554 SCV001499649 uncertain significance Familial cancer of breast 2020-04-12 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357877 SCV001553471 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.Thr476Met variant was identified in 5 of 3910 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer and non-BRCA hereditary breast cancer cases of Bulgarian and French ethnicity, and was not identified in 3244 control chromosomes from healthy individuals (Angelova 2012, Desrichard 2011, Le Calvez-Kelm 2011). However among these studies, the frequencies were not consistent and ranged from 0.01 to 0.0004. An additional large study identified the variant in 67 of 91758 proband chromsomes (freq. 0.0007) from individuals who underwent panel testing that including CHEK2 (Leedom 2016 27751358). The variant was also identified in dbSNP (ID: rs142763740) as “with likely pathogenic allele”, in ClinVar and Clinvitae databases (as likely pathogenic by GeneDx, Ambry Genetics, Illumina clinical Services, Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C, Quest Diagnostics Nichols Institute San Juan Capistrano as uncertain significance by Invitae, University of Washington Department of Laboratory Medicine and Genetic Services Laboratory, University of Chicago). The variant is further listed in the Zhejiang University database with no classification. The variant was not identified in Cosmic and MutDB databases. The same amino acid change but different nucleotide change (c.1427C>A) was observed in a patient with a clinical diagnosis of Li-Fraumeni syndrome (Sardi 2014). The variant is identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and the NHLBI GO Exome Sequencing Project in 3 of 4698 European American alleles. In addition, the variant was identified in control databases in 84 of 260146 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 6 of 22580 chromosomes (freq: 0.0003), “other” in 7 of 6276 chromosomes (freq: 0.001), Latino in 6 of 34216 chromosomes (freq: 0.0002), European Non-Finnish in 65 of 122014 chromosomes (freq: 0.0005); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. In order to evaluate mutations in all parts of the CHEK2 gene with a single biological test, an assay to evaluate CHEK2-mediated response to DNA damage was developed based on complementation of S. cerevisiae rad53 by human CHEK2. Based on growth of the strain after DNA damage, the p.Thr476Met variant was found to be damaging (Roeb 2012). The p.Thr476Met variant, which maps to the kinase domain of CHEK2, is likely to disrupt the protein function (Angelova 2012). In one study, the p.Thr476Met variant did not display kinase activity consistently and was classified as probably deleterious (Desrichard 2011). However additional functional studies are needed to determine that the p.Thr476Met variant disrupts the biological function of CHEK2. The p.Thr476 residue is conserved in in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Thr476Met variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000212465 SCV001743206 uncertain significance not provided no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV000778653 SCV001749904 not provided CHEK2-Related Cancer Susceptibility no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 11-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001564016 SCV001786717 likely pathogenic Malignant tumor of colon 2021-08-16 no assertion criteria provided clinical testing Colon Carcinoma
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001572627 SCV001792256 likely pathogenic Breast carcinoma 2021-08-19 no assertion criteria provided clinical testing Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000212465 SCV001807610 uncertain significance not provided no assertion criteria provided clinical testing

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