This sequence change affects an acceptor splice site in intron 4 of the CHEK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast, prostate, or colorectal cancer (PMID: 25186627, 29659569, 32522261, 32906215). ClinVar contains an entry for this variant (Variation ID: 216003). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.593-1G>T
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007194.4(CHEK2):c.593-1G>T
Variation ID: 216003 Accession: VCV000216003.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28719486 (GRCh38) [ NCBI UCSC ] 22: 29115474 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 16, 2017 May 1, 2024 Jan 19, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007194.4:c.593-1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001005735.2:c.722-1G>T splice acceptor NM_001257387.2:c.-71-1G>T splice acceptor NM_001349956.2:c.482+5400G>T intron variant NM_145862.2:c.593-1G>T splice acceptor NC_000022.11:g.28719486C>A NC_000022.10:g.29115474C>A NG_008150.2:g.27381G>T LRG_302:g.27381G>T LRG_302t1:c.593-1G>T - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000022.11:28719485:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| CHEK2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4053 | 4109 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 19, 2024 | RCV000195929.21 | |
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 2, 2023 | RCV000566129.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 14, 2022 | RCV002485316.3 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
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Likely pathogenic
(Jan 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253713.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 4 of the CHEK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 4 of the CHEK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast, prostate, or colorectal cancer (PMID: 25186627, 29659569, 32522261, 32906215). ClinVar contains an entry for this variant (Variation ID: 216003). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
|
Likely pathogenic
(Oct 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000666386.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The c.593-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 4 of the CHEK2 gene. This nucleotide position … (more)
The c.593-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 4 of the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. (less)
|
|
|
Likely pathogenic
(Jan 04, 2022)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002537624.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CHEK2 c.593-1G>T variant has been reported in heterozygosity in at least 4 individuals with breast prostate, colorectal and endometrial cancer (PMID: 25186627, 29659569, 32906215, … (more)
The CHEK2 c.593-1G>T variant has been reported in heterozygosity in at least 4 individuals with breast prostate, colorectal and endometrial cancer (PMID: 25186627, 29659569, 32906215, 32522261). This variant was not observed in the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 216003). This variant affects a nucleotide within a consensus splice site of an intron. This variant may cause exon skipping, intron retention or use of a cryptic splice site. 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). Based on the current evidence available, this variant is interpreted as likely pathogenic. (less)
|
|
|
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Likely pathogenic
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000839483.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
|
|
Likely pathogenic
(Apr 05, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000677829.2
First in ClinVar: Apr 16, 2017 Last updated: Dec 24, 2022 |
|
|
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Pathogenic
(Apr 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Colorectal cancer Familial prostate cancer Bone osteosarcoma Li-Fraumeni syndrome 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002792970.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Likely pathogenic
(Mar 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004020087.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either … (more)
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. (less)
|
|
|
Likely pathogenic
(Jun 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004217659.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Likely pathogenic
(Oct 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000689703.3
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G>T nucleotide substitution at the -1 position of intron 4 of the CHEK2 gene. Splice site prediction tools predict that this … (more)
This variant causes a G>T nucleotide substitution at the -1 position of intron 4 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with breast, endometrial, prostate, and colorectal cancer (PMID: 25186627, 29659569, 32522261, 32906215). 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 Likely Pathogenic. (less)
|
Comment:
Comment:
The c.593-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 4 of the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Comment:
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Comment:
This variant causes a G>T nucleotide substitution at the -1 position of intron 4 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with breast, endometrial, prostate, and colorectal cancer (PMID: 25186627, 29659569, 32522261, 32906215). 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 Likely Pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change affects an acceptor splice site in intron 4 of the CHEK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast, prostate, or colorectal cancer (PMID: 25186627, 29659569, 32522261, 32906215). ClinVar contains an entry for this variant (Variation ID: 216003). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
The c.593-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 4 of the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Comment:
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Comment:
This variant causes a G>T nucleotide substitution at the -1 position of intron 4 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with breast, endometrial, prostate, and colorectal cancer (PMID: 25186627, 29659569, 32522261, 32906215). 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 Likely Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Comprehensive analysis and ACMG-based classification of CHEK2 variants in hereditary cancer patients. | Vargas-Parra G | Human mutation | 2020 | PMID: 32906215 |
| A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection. | Velázquez C | Journal of translational medicine | 2020 | PMID: 32522261 |
| Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer. | Paulo P | PLoS genetics | 2018 | PMID: 29659569 |
| Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
| A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland. | Bąk A | Hereditary cancer in clinical practice | 2014 | PMID: 24713400 |
| Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. | Cybulski C | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21876083 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs786203229 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.