rs730881700
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_007194.4(CHEK2):βc.1368_1369insAβ(p.Glu457ArgfsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000262 in 1,602,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000033 ( 0 hom., cov: 32)
Exomes π: 0.000026 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 frameshift
NM_007194.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.439
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]
Genome browser will be placed here
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 22-28695133-C-CT is Pathogenic according to our data. Variant chr22-28695133-C-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.1368_1369insA | p.Glu457ArgfsTer33 | frameshift_variant | 12/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1368_1369insA | p.Glu457ArgfsTer33 | frameshift_variant | 12/15 | 1 | NM_007194.4 | ENSP00000385747 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152216Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
5
AN:
152216
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251012Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135666
GnomAD3 exomes
AF:
AC:
5
AN:
251012
Hom.:
AF XY:
AC XY:
3
AN XY:
135666
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000255 AC: 37AN: 1450462Hom.: 0 Cov.: 29 AF XY: 0.0000235 AC XY: 17AN XY: 722434
GnomAD4 exome
AF:
AC:
37
AN:
1450462
Hom.:
Cov.:
29
AF XY:
AC XY:
17
AN XY:
722434
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74356
GnomAD4 genome
AF:
AC:
5
AN:
152216
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74356
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:6
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 24, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 09, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 02, 2018 | Variant summary: CHEK2 c.1368dupA (p.Glu457ArgfsX33) 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. At least one publication reports experimental evidence evaluating an impact on protein function, which demonstrated that the truncated protein product is localizes exclusively to the cytoplasm, suggesting the 1368dupA mutant to be nonfunctional, as the main substrates for CHK2 phosphorylation are located in the nucleus (Staalesen 2004). The variant allele was found at a frequency of 2.4e-05 in 245848 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (2.4e-05 vs 0.00031), allowing no conclusion about variant significance; moreover pseudogene interference might also affect the validity of these frequency results. c.1368dupA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Tung 2016, Susswein 2016, Leedom 2016). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Feb 26, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Glu457Argfs*33) 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 (rs730881700, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312, 26976419, 28724667). ClinVar contains an entry for this variant (Variation ID: 182450). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 14, 2023 | 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27751358, 30322717, 26689913, 29625052, 26681312, 26976419, 29356917, 28724667, 30487145, 31060593, 32906215, 33925588, 32805687, 29922827, 34308104) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | CHEK2: PVS1, PM2, PS4:Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 08, 2021 | This frameshift variant causes the premature termination of CHEK2 protein synthesis. It has been reported in individuals affected with breast cancer in the published literature (PMID: 28724667 (2017), 26976419 (2016), 26681312 (2015), 15361853 (2004)). Additionally, tumor staining and in vitro analysis found that the truncated protein was mislocalized and found only in the cytoplasm, thus confirming a damaging effect of this variant on CHEK2 protein function (PMID: 15361853 (2004)). The frequency of this variant in the general population is consistent with pathogenicity. Therefore, the variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 05, 2023 | This variant inserts 1 nucleotide in exon 12 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. This variant has been reported in multiple individuals affected with breast cancer (PMID: 26681312, 26976419, 28724667, 33925588; Color internal data). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 5/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000164). This variant has been identified in 5/251012 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 | Oct 15, 2021 | The c.1368dupA pathogenic mutation, located in coding exon 11 of the CHEK2 gene, results from a duplication of A at nucleotide position 1368, causing a translational frameshift with a predicted alternate stop codon (p.E457Rfs*33). In a cohort of 488 consecutive patients with breast cancer that underwent next generation sequencing of 25 cancer predisposition genes, this mutation was identified in one non-Ashkenazi Jewish woman who was diagnosed at age 42 (Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8). This mutation has also been reported in 6 individuals from a cohort of 45879 patients who underwent multi-gene panel testing including CHEK2 (Leedom TP et al. Cancer Genet. 2016 Sep;209:403-407), in 1 of 10030 individuals undergoing hereditary cancer panel testing through a clinical laboratory (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32), and in 1 of 8085 consecutive unrelated Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). 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 06, 2021 | - - |
CHEK2-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 19, 2024 | The CHEK2 c.1368dupA variant is predicted to result in a frameshift and premature protein termination (p.Glu457Argfs*33). This variant was reported in individuals with breast cancer (Table S1, Susswein et al. 2016. PubMed ID: 26681312; Table S3, Sun et al. 2017. PubMed ID: 28724667), ovarian cancer (Table S1, Carter et al. 2018. PubMed ID: 30322717), and colorectal cancer (referred to as c.1497_1498insA in Table S1, DeRycke et al. 2017. PubMed ID: 28944238). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182450/). Frameshift variants in CHEK2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
CHEK2-related cancer predisposition Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Snyder Lab, Genetics Department, Stanford University | Jan 01, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at