ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1596del (p.Thr533fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007194.4(CHEK2):c.1596del (p.Thr533fs)
Variation ID: 141133 Accession: VCV000141133.22
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28687933 (GRCh38) [ NCBI UCSC ] 22: 29083921 (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 Sep 24, 2016 Jun 17, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.1596del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Thr533fs frameshift NM_007194.4:c.1596delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001005735.2:c.1725del NP_001005735.1:p.Thr576fs frameshift NM_001257387.2:c.933del NP_001244316.1:p.Thr312fs frameshift NM_001349956.2:c.1395del NP_001336885.1:p.Thr466fs frameshift NM_007194.3:c.1596del NM_145862.2:c.1509del NP_665861.1:p.Thr504fs frameshift NC_000022.11:g.28687934del NC_000022.10:g.29083922del NG_008150.2:g.58934del LRG_302:g.58934del LRG_302t1:c.1596del LRG_302p1:p.Thr533fs - Protein change
- T312fs, T504fs, T533fs, T466fs, T576fs
- Other names
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- Canonical SPDI
- NC_000022.11:28687932:GG:G
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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CHEK2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3989 | 4043 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 21, 2023 | RCV000129505.12 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Sep 17, 2023 | RCV000205993.14 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV000235161.9 |
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
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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
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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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Uncertain significance
(Sep 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000259557.10
First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 141133). This frameshift has been observed in individual(s) with breast cancer (PMID: 30303537). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change results in a frameshift in the CHEK2 gene (p.Thr533Glnfs*33). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the CHEK2 protein and extend the protein by 21 additional amino acid residues. (less)
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Uncertain significance
(Nov 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001343030.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 1 nucleotide in exon 15 of the CHEK2 gene, creating a frameshift at codon 533, replacing the last 11 amino acids and … (more)
This variant deletes 1 nucleotide in exon 15 of the CHEK2 gene, creating a frameshift at codon 533, replacing the last 11 amino acids and extends the length of the encoded protein by 21 amino acids. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial breast cancer who lack pathogenic variants in the BRCA1 or BRCA2 gene (PMID: 30303537) and in an individual with early-onset breast cancer (Color data). This variant has been identified in 3/265102 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Oct 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000785624.2
First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018 |
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Uncertain significance
(May 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000211015.15
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation as the last 11 amino acids are … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation as the last 11 amino acids are replaced with 32 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Observed in individuals with breast cancer (Girard 2019); This variant is associated with the following publications: (PMID: 29615459, 30303537) (less)
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Uncertain significance
(Sep 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000184277.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.1596delC variant, located in coding exon 14 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1596, causing a … (more)
The c.1596delC variant, located in coding exon 14 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1596, causing a translational frameshift with a predicted alternate stop codon (p.T533Qfs*33). This alteration was identified in 2/1207 cases of French women diagnosed with breast cancer who had a sister with breast cancer and were BRCA1 and BRCA2 negative and 0/1199 general population controls (Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This deletion and subsequent frameshift occur near the 3' terminus of CHEK2 and result in removal of the last 11 amino acids of CHK2 and insertion of 32 amino acids to the C-terminus, resulting in the elongation of the protein by 21 amino acids. The exact functional impact of these inserted amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004810721.3
First in ClinVar: Apr 15, 2024 Last updated: Jun 17, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Aug 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556498.2
First in ClinVar: Aug 04, 2022 Last updated: Dec 17, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. | Girard E | International journal of cancer | 2019 | PMID: 30303537 |
Text-mined citations for rs587781519 ...
HelpRecord last updated Jun 17, 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.