ClinVar Miner

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

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Total submissions: 14
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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 2017-07-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Functionally-validated splicing mutation
Invitae RCV000196718 SCV000253902 pathogenic Familial cancer of breast 2018-12-28 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 RCV000116017 SCV000537642 pathogenic Hereditary cancer-predisposing syndrome 2015-03-11 criteria provided, single submitter clinical testing
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 2018-08-01 criteria provided, single submitter clinical testing
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 ( 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.
Integrated Genetics/Laboratory Corporation of America 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

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