ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.444+1G>A (rs121908698)

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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212418 SCV000149926 pathogenic not provided 2018-08-30 criteria provided, single submitter clinical testing This pathogenic variant is denoted CHEK2 c.444+1G>A or IVS3+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 3 of the CHEK2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. A splicing assay showed this variant resulted in the use of an alternate splice donor site, subsequently producing a prematurely truncated protein (Dong 2003). This variant, previously reported as IVS2+1G>A using alternate nomenclature, is considered a Polish founder pathogenic variant and has been observed in association with familial prostate, breast and gastric cancer (Dong 2003, Cybulski 2006, Teodorczyk 2013, Bak 2014). Cybulski et al. (2004) noted a significant association with thyroid cancer for this splicing variant. Based on the current evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000116017 SCV000186195 pathogenic Hereditary cancer-predisposing syndrome 2018-07-10 criteria provided, single submitter clinical testing The c.444+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the CHEK2 gene. This mutation has been described in numerous breast cancer patients, including individuals with bilateral breast cancer (Kraus C et al. Int. J. Cancer 2017 Jan;140(1):95-102; Pelttari LM et al. Clin. Genet. 2018 Mar;93(3):595-602). In addition, this mutation has been associated with increased risk of breast, prostate, thyroid, and stomach cancers as well as polycythaemia vera in Polish patient cohorts (Cybulski C et al. Am. J. Hum. Genet. 2004 Dec;75:1131-5; Serrano-Fernandez P et al. Breast Cancer Res. Treat. 2009 Sep;117:161-5; Cybulski C et al. J. Clin. Oncol. 2011 Oct;29:3747-52; Teodorczyk U et al. Fam. Cancer. 2013 Sep;12:473-8; Janiszewska H et al. Br. J. Haematol. 2016 Apr;173(1):150-2). Of note, this alteration is also designated as IVS2+1G>A in published literature. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000196718 SCV000253902 pathogenic Familial cancer of breast 2020-10-29 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the CHEK2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs121908698, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant is well-described in the literature. In multiple studies, women heterozygous for this variant have an increased risk (OR=2.3-3.5) for familial breast cancer (PMID: 24713400, 15492928, 19030985, 21876083), while men with this variant have an increased risk (OR=2.5) for prostate cancer (PMID: 12533788, 15492928). Increased risks of melanoma (OR=3.3), stomach (OR=3.5), and thyroid (OR=6.2) cancer have also been reported (PMID: 15492928). This variant is also known as IVS2+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 128075). Experimental studies have shown that this variant results in aberrant splicing and a marked decrease in CHEK2 protein expression (PMID: 12533788). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000210090 SCV000266069 pathogenic Breast and colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
Counsyl RCV000196718 SCV000488172 likely pathogenic Familial cancer of breast 2016-01-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000116017 SCV000537642 pathogenic Hereditary cancer-predisposing syndrome 2020-10-07 criteria provided, single submitter clinical testing This variant (also known as IVS2+1G>A) causes a G to A nucleotide substitution at the +1 position of intron 3 of the CHEK2 gene. A functional study has shown that this variant abolishes the native splice donor site and activates a cryptic splice site, which leads to a frameshift and premature protein truncation (PMID: 12533788, 31843900). As a result, CHEK2 protein expression levels were significantly reduced (PMID: 12533788). This variant has been reported in numerous individuals affected with cancer and is particularly associated with familial breast cancer (PMID: 15095295, 15492928, 19030985, 21876083, 24713400) and prostate cancer (PMID: 12533788, 15087378). The variant considered to be a founder mutation in the Polish population (PMID: 15087378, 15492928). This variant has been identified in 40/282678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000501923 SCV000594120 pathogenic Breast cancer, susceptibility to 2016-09-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212418 SCV000601168 pathogenic not provided 2017-02-11 criteria provided, single submitter clinical testing
GeneKor MSA RCV000212418 SCV000821730 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This variation occurs one base after exon 3 of the CHEK2 gene in a position highly conserved in the human and other genomes that is crucial for mRNA processing. This is expected to result in incorrect splicing and likely results in an absent or disrupted protein product. This variant has been reported in literature in individuals with increased risk for breast, prostate and other cancers (PMID:15492928, PMID: 19030985, PMID:12533788, PMID: 15492928). This variant is also known as IVS2+1G>A in the literature. The mutation database ClinVar contains entries for this variant (Variation ID: 128075). Algorithms developed to predict the effect of single base changes on mRNA splicing suggest that this variant may alter this cellular process. Moreover, experimental studies support the pathogenic effect of this variant through in mRNA splicing (PMID: 12533788).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000196718 SCV000839944 pathogenic Familial cancer of breast 2017-05-25 criteria provided, single submitter clinical testing This c.444+1G>A variant in the CHEK2 gene has been reported in patients with breast cancer [PMID 21876083, 27616075, 26822949, 24713400 referred as IVS2+1G>A]. This variant was also reported in a cohort of patients with thyroid cancer [PMID 25583358], prostate cancer [PMID 12533788] and multiple types of cancer [PMID 15492928]. This variant was also detected in one patient with breast cancer who was compound heterozygous for this c.444+1G>A variant and the p.I157T pathogenic variant [PMID 2471340]. This variant affects the invariant donor splice site of intron 3 of the CHEK2 gene. While not validated for clinical use, computer-based algorithms predict this c.444+1G>A change to disrupt this splicing site. This variant was detected in 14 heterozygous individuals within the ExAC database (http://exac.broadinstitute.org/variant/22-29121230-C-T). This variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763475 SCV000894257 pathogenic Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779368 SCV000915969 likely pathogenic CHEK2-Related Cancer Susceptibility 2018-09-21 criteria provided, single submitter clinical testing The CHEK2 c.444+1G>A variant, also reported as IVS2+1G>A, occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant is well described in the literature in over 100 probands, and is associated particularly with familial prostate cancer and breast cancer (Dong et al. 2003, Cybulski et al. 2004a, Cybulski et al. 2004b, Cybulski et al. 2011, Bąk et al. 2014, Borun et al. 2015, Siołek et al. 2015) with odds ratios for familial prostate cancer of up to 12.1 (Cybulski et al. 2004b) and breast cancer of 3.0 (Bąk et al. 2014). The c.444+1G>A variant is reported at a frequency of 0.000465 in the European (non-Finnish) population of the Genome Aggregation Database. The c.444+1G>A variant has been shown to be one of three CHEK2 founder variants in the Polish population. Functional studies by Dong et al. (2003) demonstrated that the c.444+1G>A variant creates a premature stop codon, which removes part of the FHA domain of the protein and the entire kinase activation domain, and western blot analysis showed dramatic reduction of CHEK2 protein levels in cell lines from the proband. Based on the evidence, the c.444+1G>A variant is classified as likely pathogenic for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000196718 SCV000917232 pathogenic Familial cancer of breast 2017-11-22 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.444+1G>A variant involves the alteration of a conserved intronic nucleotide that is the first nucleotide of the intron at an exon-intron junction. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a loss of the canonical splice site, which is supported by functional studies that show the use of a cryptic splice site in patient cell lines that introduces 4bp, thus causing a frameshift. A concomitant reduction in CHEK2 protein was also detected in these patient cell lines, supporting the splicing data (Dong_2003). The variant has been identified in numerous patients with breast and prostate cancer (Kraus_2016, Maxwell_2016, Lhota_2016). The variant reportedly identified among BrC patients at a frequency of 1.3% and is considered to be one of the four founder mutations in Poland (Cybulski_2011). This variant was found in 39/278078 control chromosomes at a frequency of 0.0001402, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics RCV000196718 SCV001141371 pathogenic Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212418 SCV001245716 pathogenic not provided 2021-01-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000196718 SCV001366166 pathogenic Familial cancer of breast 2020-02-13 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4.
Institute of Human Genetics, University of Leipzig Medical Center RCV000196718 SCV001440944 pathogenic Familial cancer of breast 2019-01-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000212418 SCV001446511 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Department of Pediatrics,Memorial Sloan Kettering Cancer Center RCV000196718 SCV001478115 pathogenic Familial cancer of breast 2020-12-15 criteria provided, single submitter research
Department of Pediatric Oncology, Hematology and Clinical Immunology,University Clinics Duesseldorf RCV000116017 SCV001482300 uncertain significance Hereditary cancer-predisposing syndrome criteria provided, single submitter research
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000196718 SCV001499789 pathogenic Familial cancer of breast 2020-04-02 criteria provided, single submitter clinical testing
King Laboratory,University of Washington RCV001171461 SCV001251372 pathogenic Familial cancer of breast; Li-Fraumeni syndrome 2 2019-09-01 no assertion criteria provided research
CZECANCA consortium RCV001270936 SCV001451740 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354639 SCV001549303 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 c.444+1G>A variant was identified in 179 of 121122 proband chromosomes (frequency: 0.002) from individuals or families with ascertained in studies of various cancers and was present in 23 of 11230 control chromosomes (frequency: 0.002) from healthy individuals (Bak 2014, Cybulski 2004, Cybulski 2011, Dong 2003, Havranek 2015, Janiszewska 2016, Leedom 2016, Sioek 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs121908698) as With Pathogenic allele, and ClinVar (classified as pathogenic by GeneDx, Ambry Genetics, Invitae, Color Genomics and two clinical laboratories; classified as likely benign by Counsyl). The variant was not identified in Zhejiang Colon Cancer Database. The variant was identified in control databases in 39 of 277022 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: Other in 3 of 6464 chromosomes (freq: 0.001), European Non-Finnish in 24 of 126516 chromosomes (freq: 0.0002), European Finnish in 12 of 25792 chromosomes (freq: 0.001), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The c.444+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. The c.444+1G>A variant was shown to results in a 4-bp insertion due to an abnormal splicing, using an alternative splice donor site in intron 2. This variant eliminates part of forkhead-homology associated domain and the entire kinase activation domain of CHEK2 (Dong 2003, Havranek 2015). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000212418 SCV001740519 pathogenic not provided no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV000779368 SCV001749588 not provided CHEK2-Related Cancer Susceptibility no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 06-11-2020 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 RCV001554253 SCV001774858 pathogenic Breast carcinoma 2021-08-09 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000212418 SCV001809764 likely pathogenic not provided no assertion criteria provided clinical testing

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