22-28725242-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1PP3PP5_Very_Strong
The NM_007194.4(CHEK2):c.444+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000905 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000091 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 splice_donor, intron
NM_007194.4 splice_donor, intron
Scores
1
3
3
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.03
Genes affected
CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.6, offset of 4, new splice context is: tagGTaatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PP3
Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, Dann, MutationTaster was below the threshold]
PP5
Variant 22-28725242-C-T is Pathogenic according to our data. Variant chr22-28725242-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725242-C-T is described in Lovd as [Pathogenic]. Variant chr22-28725242-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000854 AC: 13AN: 152148Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000131 AC: 33AN: 251274Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135796
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GnomAD4 exome AF: 0.0000910 AC: 133AN: 1461812Hom.: 0 Cov.: 32 AF XY: 0.0000935 AC XY: 68AN XY: 727210
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GnomAD4 genome 0.0000854 AC: 13AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74432
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:54Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:16
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2020 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25980754, 25583358, 15095295, 27751358, 28918466, 30322717, 30927251, 31159747, 33077847, 32885271, 32338768, 33726816, 21876083, 25525159, 25915596, 26083025, 26250988, 25619955, 26084796, 15492928, 22058216, 19030985, 23296741, 26822949, 27153395, 26629066, 26929905, 26296701, 27038244, 24713400, 12533788, 16914568, 27616075, 27783279, 28727877, 28802053, 15810020, 27488870, 28680382, 28211887, 29356917, 29067458, 17085682, 29520813, 29902706, 29958926, 26681312, 30426508, 31447099, 34308366, 34570182) - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 02, 2021 | This variant disrupts a canonical splice-donor site and interferes with normal CHEK2 mRNA splicing. In the published literature, the variant has been reported in individuals and families with hereditary cancer (PMIDs: 28779002 (2017), 25583358 (2015), 24713400 (2014), 21876083 (2011), and 15492928 (2004)). The frequency of this variant in the general population, 0.00052 (13/25122 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 24, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | CHEK2: PVS1, PS4, PM2:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 22, 2023 | The CHEK2 c.444+1G>A variant (rs121908698), also known as IVS2+1G>A, is reported in numerous individuals with familial breast cancer and prostate cancer, and is considered to be one of three CHEK2 founder variants in the Polish population (Bak 2014, Cybulski 2004, Cybulski 2006, Dong 2003). Functional analysis showed that this variant results in a 4-bp insertion due to abnormal splicing and creates a premature termination codon eliminating part of the FHA domain and the entire kinase activation domain of CHEK2 (Dong 2003). This variant is reported in ClinVar (Variation ID: 128075). It is observed in the general population with an overall allele frequency of 0.01% (40/282678 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: Bak A et al. A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland. Hered Cancer Clin Pract. 2014 Apr 8;12(1):10. PMID: 24713400. Cybulski C et al. A novel founder CHEK2 mutation is associated with increased prostate cancer risk. Cancer Res. 2004 Apr 15;64(8):2677-9. PMID: 15087378. Cybulski C et al. CHEK2-positive breast cancers in young Polish women. Clin Cancer Res. 2006 Aug 15;12(16):4832-5. PMID: 16914568. Dong X et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003 Feb;72(2):270-80. PMID: 12533788. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 10, 2023 | PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Oct 13, 2023 | - - |
Familial cancer of breast Pathogenic:16
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 24, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 22, 2017 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Sep 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 23, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | May 25, 2017 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 17, 2020 | - - |
| Pathogenic, criteria provided, single submitter | research | Department of Pediatrics, Memorial Sloan Kettering Cancer Center | Dec 15, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2025 | This sequence change affects a donor splice site in intron 3 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs121908698, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with an increased risk (OR=2.3-3.5) for familial breast cancer or an increased risk (OR=2.5) for prostate cancer (PMID: 15492928, 19030985, 24713400; 21876083 12533788). This variant is also known as IVS2+1G>A. ClinVar contains an entry for this variant (Variation ID: 128075). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 12533788; internal data). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 09, 2023 | This variant is considered pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | research | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 09, 2022 | PVS1, PS3, PS4_STR, BS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory Cellgenetics, GMDL Cellgenetics | Mar 01, 2022 | The variant CHEK2:c.444+1G>A was classified as Pathogenic. The classification was assigned based on the following ACMG criteria: PVS1, PS3, PS4_moderate, PM2, PP5. - |
Hereditary cancer-predisposing syndrome Pathogenic:4Uncertain:1
| Uncertain significance, flagged submission | research | Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Feb 04, 2025 | PVS1; PS4 - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 30, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 05, 2023 | This variant causes a G to A nucleotide substitution at the +1 position of intron 3 of the CHEK2 gene. It is also known as CHEK2 IVS2+1G>A in the literature. RNA studies have 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). This variant has been reported in numerous individuals affected breast cancer (PMID: 15095295, 15492928, 21876083, 24713400, 33030641), ovarian cancer (PMID: 32546565), and prostate cancer (PMID: 12533788, 15087378). A large case-control study has shown that this variant is associated with an increased risk of breast cancer (OR=2.085, 95%CI [1.34 to 3.245], PMID: 33471991). The variant is thought 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 31, 2024 | 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 multiple individuals diagnosed with 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 polycythemia 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. - |
CHEK2-related cancer predisposition Pathogenic:2Other:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 21, 2018 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant is also referred to as IVS2+1G>A in the literature. The c.573+1G>A variant affects the canonical splice donor site of intron 4 and is therefore predicted to interfere with splicing and result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with familial prostate cancer and breast cancer with odds ratios for familial prostate cancer of up to 12.1 and breast cancer of 3.0 (PMID: 12533788, 15492928, 21876083, 24713400, 25583358). This variant has also been associated with increased risk of other cancers including colon, thyroid and ovarian cancer and polycythemia vera (PMID: 15492928, 26084796, 26681312, 30322717). RNA analysis of cell lines derived from patient cells demonstrated that this variant results in reduced protein levels and use of another splice donor site, leading to frameshift and creation of a premature termination codon (PMID: 12533788). It is present in the heterozygous state in the gnomAD population database at a frequency of .014% (40/282678) and thus is presumed to be rare. Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. Based on the available evidence, the c.573+1G>A variant is classified as Pathogenic. - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | 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. - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 16, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
CHEK2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 27, 2024 | The CHEK2 c.444+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant (previously known as IVS2+1G>A) has been reported to be associated with predisposition to hereditary non-polyposis colorectal cancer (Yurgelun et al. 2015. PubMed ID: 25980754), an increased risk of breast and prostate cancer in Eastern European populations, and shows co-segregation with disease with a weakly penetrant effect (Dong et al. 2003. PubMed ID: 12533788; Cybulski et al. 2004. PubMed ID: 15492928; Cybulski et al. 2011. PubMed ID: 21876083; Lhota et al. 2016. PubMed ID: 26822949). It was also reported in patients with essential thrombocythemia diagnosed after age 57 (Janiszewska et al. 2012. PubMed ID: 22058216). This variant is reported in 0.052% of alleles in individuals of European (Finnish) descent in gnomAD. In ClinVar, the vast majority of labs consider this variant pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/128075/). Variants that disrupt the consensus splice donor site in CHEK2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Inherited breast cancer and ovarian cancer Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Oct 29, 2024 | PVS1,PM5_Supporting - |
Familial cancer of breast;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C5882668:Li-Fraumeni syndrome 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:Li-Fraumeni syndrome 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 14, 2024 | - - |
Breast and colorectal cancer, susceptibility to Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
Breast carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 09, 2021 | - - |
Li-Fraumeni syndrome 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 12, 2024 | Criteria applied: PVS1,PS4,PS1_SUP - |
Breast cancer, susceptibility to Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 29, 2016 | - - |
Colorectal cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Aug 17, 2022 | ACMG criteria used to clasify this variant: PVS1, PM2, PS4 - |
Melanoma Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Dec 05, 2022 | ACMG criteria used to clasify this variant: PVS1, PM2, PS4 - |
Familial cancer of breast;C5882668:Li-Fraumeni syndrome 2 Pathogenic:1
| Pathogenic, no assertion criteria provided | research | King Laboratory, University of Washington | Sep 01, 2019 | - - |
TUMOR PREDISPOSITION SYNDROME 4, BREAST/PROSTATE Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2006 | - - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Endometrial carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Feb 21, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -3
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at