rs786203458
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_007194.4(CHEK2):โc.277delTโ(p.Trp93fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000479 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (โ โ ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes ๐: 0.0000048 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 frameshift
NM_007194.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.92
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 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 22-28734444-CA-C is Pathogenic according to our data. Variant chr22-28734444-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 187085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734444-CA-C is described in Lovd as [Pathogenic]. Variant chr22-28734444-CA-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.277delT | p.Trp93fs | frameshift_variant | 2/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.277delT | p.Trp93fs | frameshift_variant | 2/15 | 1 | NM_007194.4 | ENSP00000385747.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
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31
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461798Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727190
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:16Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Mar 29, 2023 | PS4_MOD, PVS1, PM2_SUP - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 13, 2023 | The CHEK2 c.277del (p.Trp93Glyfs*17) variant alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. This variant has been reported in the published literature in multiple individuals with breast cancer (PMID: 26822949 (2016), 30093976 (2018), 30128536 (2018), 30303537 (2019), 33471991 (2021)), including an individual with both breast cancer and melanoma (PMID: 26681312 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | CHEK2: PVS1, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 01, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30303537, 26681312, 26822949, 27751358, 30093976, 31050813, 30875412, 34903604) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 11, 2021 | - - |
Familial cancer of breast Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 08, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 08, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 04, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 06, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | This sequence change creates a premature translational stop signal (p.Trp93Glyfs*17) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26822949, 30093976). ClinVar contains an entry for this variant (Variation ID: 187085). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 25, 2022 | This variant deletes 1 nucleotide in exon 2 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has been reported in individuals affected with breast cancer in the literature (PMID: 26681312, 26822949, 30875412, 30093976, 31050813, 30303537). This variant has not been identified 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 | Sep 22, 2024 | The c.277delT pathogenic mutation, located in coding exon 1 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 277, causing a translational frameshift with a predicted alternate stop codon (p.W93Gfs*17). This mutation has been reported in multiple individuals with breast cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Lhota F et al. Clin. Genet. 2016 Oct;90:324-33; Cybulski C et al. J Clin Oncol 2011 Oct;29(28):3747-52; Kleiblova P et al. Int J Cancer 2019 10;145(7):1782-1797). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 25, 2021 | - - |
Li-Fraumeni syndrome 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 07, 2022 | _x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP - |
Predisposition to cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 22, 2024 | The CHEK2 c.277del (p.Trp93GlyfsTer17) deletes one nucleotide to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in individuals with breast cancer (PMID: 26822949, 26681312, 30093976, 30303537, 30875412, 34326862, 35534704). It is also absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 05, 2022 | Variant summary: CHEK2 c.277delT (p.Trp93GlyfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251224 control chromosomes. c.277delT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (eg. Lhota_2016, Kleiblova_2019, Lu_2018). These data indicate that the variant is very likely to be associated with disease. Co-occurrence with another (likely) pathogenic variant was reported in one of these patients (CHEK2 c.444+1G>A, p.E149fs*6), although other patients with similar diagnoses did not have such co-occurrences (Kleiblova_2019). One publication reports experimental evidence evaluating an impact on protein function, showing a large reduction in phosphorylating activity on the target Kap1 (Boonen_2022). 11 laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
CHEK2-related cancer predisposition Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 11-17-2020 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. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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