rs587781269
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_007194.4(CHEK2):c.283C>T(p.Arg95Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000508 in 1,613,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 stop_gained
NM_007194.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.67
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 22-28734439-G-A is Pathogenic according to our data. Variant chr22-28734439-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 140772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734439-G-A is described in Lovd as [Pathogenic]. Variant chr22-28734439-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.283C>T | p.Arg95Ter | stop_gained | 2/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.283C>T | p.Arg95Ter | stop_gained | 2/15 | 1 | NM_007194.4 | ENSP00000385747 | P2 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 151994Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251218Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135790
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GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461770Hom.: 0 Cov.: 33 AF XY: 0.0000481 AC XY: 35AN XY: 727178
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:20Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2023 | This sequence change creates a premature translational stop signal (p.Arg95*) 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 present in population databases (rs587781269, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer or prostate cancer (PMID: 18725978, 21244692, 27708748). ClinVar contains an entry for this variant (Variation ID: 140772). 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 creates a termination codon and is predicted to result in premature protein truncation. - |
| 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 | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jun 05, 2017 | This c.283C>T (p.Arg95*) variant in the CHEK2 gene has been reported in two patients from Norway with advanced breast cancer [PMID 18725978]. The c.283C>T (p.Arg95*) variant was subsequently detected in 12 individuals from a case control study: 4 from the control group (no cancer), 4 had prostate cancer and 4 had breast cancer [PMID 27708748]. The variant was also detected in a cohort of patients with breast cancer [PMID 21244692]. This c.283C>T creates a stop codon at amino acid position 95 of the CHEK2 protein (p.Arg95*), which is predicted to results in a loss of function of the protein. This variant has been observed in 2 heterozygous individuals in the ExAC population database (http://exac.broadinstitute.org/variant/22-29130427-G-A). It is thus interpreted as a pathogenic variant - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 19, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 15, 2018 | Variant summary: The CHEK2 c.283C>T (p.Arg95X) variant results in a premature termination codon, predicted to cause a truncated or absent CHEK2 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 (e.g. c.1100delC, p.Thr367fsX15; c.1263delT, p.Ser422fsX15; c.1555C>T, p.Arg519X). One in silico tool predicts a damaging outcome for this variant. One study showed lack of dimerization of this variant with the WT Chk2 protein as well as no kinase activity (Chrisanthar_2008). This variant was found in 6/255878 control chromosomes at a frequency of 0.0000234, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284). This variant was reported in multiple patients with breast, prostate, and colorectal cancer (Knappskog_2016, Calvez-Kelm_2011, Cragun_2014), most frequently in patients of Norwegian descent . 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 | Counsyl | May 23, 2017 | - - |
not provided Pathogenic:5
| Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
| 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 | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2022 | CHEK2: PVS1:Strong, PM2, PS3:Moderate, PS4:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 26, 2022 | Nonsense 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; Observed in individuals with CHEK2-related cancers (Chrisanthar et al., 2008; Le Calvez-Kelm et al., 2011; Knappskog et al., 2016; Decker et al., 2017; Raskin et al., 2017; Li et al., 2019; Petridis et al., 2019); Published functional studies demonstrate a damaging effect: absent kinase activity (Chrisanthar et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32980694, 32805687, 32923877, 29922827, 18725978, 27708748, 24763289, 24879340, 25525159, 29212164, 21244692, 27751358, 28779002, 28944238, 29752822, 29915322, 29470806, 29520813, 31263054, 31050813, 31360903, 32091409, 31447099, 32029870, 31214711) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 04, 2020 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. The variant was found in at least one symptomatic patient and found in general population data that is consistent with pathogenicity. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 24, 2021 | The p.R95* pathogenic mutation (also known as c.283C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 283. This changes the amino acid from an arginine to a stop codon within coding exon 1. This mutation has been detected in multiple breast cancer cohorts (Chrisanthar R et al. PLoS ONE, 2008 Aug;3:e3062; Le Calvez-Kelm F et al. Breast Cancer Res, 2011 Jan;13:R6; Knappskog S et al. Hered Cancer Clin Pract, 2016 Sep;14:19; Decker B et al. J Med Genet, 2017 11;54:732-741; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Li JY et al. Int J Cancer, 2019 01;144:281-289; Petridis C et al. Cancer Epidemiol Biomarkers Prev, 2019 07;28:1162-1168; Mandelker D et al. JNCI Cancer Spectr, 2019 Jun;3:pkz027; Hata C et al. J Hum Genet, 2020 Jul;65:577-587; Chen B et al. Aging (Albany NY), 2020 02;12:3140-3155). In one case control study, this variant was reported in 8/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been detected in patients with colorectal cancer (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463) as well as prostate cancer (Knappskog S et al. Hered Cancer Clin Pract, 2016 Sep;14:19; Wu Y et al. Prostate, 2018 06;78:607-615; Mijuskovic M et al. Br J Cancer, 2018 07;119:96-104; Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 06, 2022 | This variant changes 1 nucleotide in exon 2 of the CHEK2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals affected with breast cancer (PMID: 18725978, 21244692, 27028851, 27708748, 28779002), colorectal cancer (PMID: 24506336) and prostate cancer (PMID: 27708748), as well as in several unaffected individuals (PMID: 27708748). This variant has been identified in 2/251218 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. - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 30, 2019 | The CHEK2 c.283C>T; p.Arg95Ter variant (rs587781269) is described in the literature in individuals with breast, prostate, or colorectal cancer (Chrisanthar 2008, DeRycke 2017, Knappskog 2016, Le Calvez-Kelm 2011, Li 2019, Raskin 2017, Singh 2018). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 140772). It is found in the general population with a low overall allele frequency of 0.0008% (2/251218 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Chrisanthar R et al. CHEK2 mutations affecting kinase activity together with mutations in TP53 indicate a functional pathway associated with resistance to epirubicin in primary breast cancer. PLoS One. 2008 Aug 26;3(8):e3062. DeRycke MS et al. Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. Mol Genet Genomic Med. 2017 Jul 23;5(5):553-569. Knappskog S et al. Prevalence of the CHEK2 R95* germline mutation. Hered Cancer Clin Pract. 2016 Sep 27;14:19. Le Calvez-Kelm F et al. Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res. 2011 Jan 18;13(1):R6. Li JY et al. Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. Int J Cancer. 2019 Jan 15;144(2):281-289. Raskin L et al. Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort. Oncotarget. 2017 Jun 21;8(55):93450-93463. Singh J et al. Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. Breast Cancer Res Treat. 2018 Jul;170(1):189-196. - |
CHEK2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 19, 2024 | The CHEK2 c.283C>T variant is predicted to result in premature protein termination (p.Arg95*). This variant has been reported in individuals with breast, ovarian, prostate, and colorectal cancer, but has also been reported at low frequencies in unaffected individuals (Chrisanthar et al. 2008. PubMed ID: 18725978; Knappskog et al. 2016. PubMed ID: 27708748; Raskin et al. 2017. PubMed ID: 29212164, Table S2; Singh et al. 2018. PubMed ID: 29470806, Table S2; Wu et al. 2018. PubMed ID: 29520813, Table 2; Li et al. 2018. PubMed ID: 29752822, Table S4). Although found in several ancestral populations, it has been reported as potential founder variant in individuals of Norwegian ancestry (Knappskog et al. 2016. PubMed ID: 27708748). In vitro experimental studies suggests that this variant leads to loss of CHEK2 protein dimerization and kinase activity (Chrisanthar et al. 2008. PubMed ID: 18725978). This variant is reported in 2 of ~251,000 alleles in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140772/). Nonsense variants in CHEK2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Familial cancer of breast;C0346629:Colorectal cancer;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 | Jul 21, 2021 | - - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHEK2 p.Arg95X variant was identified in 10 of 21084 proband chromosomes (frequency: 0.00047) from individuals or families with breast and prostate cancer (Knappskog_2016_27708748, Le Calvez-Kelm_2011_21244692, Wu_2018_29520813). The variant was also identified in dbSNP (ID: rs587781269) as “with pathogenic allele”, ClinVar (as pathogenic by Ambry Genetics, GeneDx, Invitae, Counsyl and Mayo), Clinvitae (3x as in ClinVar), and Zhejiang Colon Cancer Database (2x in primary breast cancer). The variant was not identified in Cosmic, and MutDB databases. The variant was identified in control databases in 2 of 246164 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European (Non-Finnish) in 1 of 111644 chromosomes (freq: 0.000009), and South Asian in 1 of 30776 chromosomes (freq: 0.000032), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or European (Finnish) populations. In a study of cancer patients in Norway, two individuals affected with breast cancer were found to carry this variant; in both patients carrying the variant, these tumours were non-responsive to epirubicin therapy (Chrisanthar_2008_18725978). In addition, the p.Arg95Ter variant protein was found to be unable to form dimers with wild-type CHEK2, and the variant was totally devoid of any CHEK2 kinase activity (Chrisanthar_2008_18725978). The p.Arg95X variant leads to a premature stop codon at position 95 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
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 03-02-2017 by Lab Myriad. 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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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
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Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;D
Vest4
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at