ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1568G>A (p.Arg523His)
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.
Uncertain significance(6); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007194.4(CHEK2):c.1568G>A (p.Arg523His)
Variation ID: 460810 Accession: VCV000460810.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28687961 (GRCh38) [ NCBI UCSC ] 22: 29083949 (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 Oct 10, 2018 Sep 16, 2024 Jul 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.1568G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Arg523His missense NM_001005735.2:c.1697G>A NP_001005735.1:p.Arg566His missense NM_001257387.2:c.905G>A NP_001244316.1:p.Arg302His missense NM_001349956.2:c.1367G>A NP_001336885.1:p.Arg456His missense NM_145862.2:c.1481G>A NP_665861.1:p.Arg494His missense NC_000022.11:g.28687961C>T NC_000022.10:g.29083949C>T NG_008150.2:g.58906G>A LRG_302:g.58906G>A LRG_302t1:c.1568G>A LRG_302p1:p.Arg523His - Protein change
- R523H, R456H, R302H, R494H, R566H
- Other names
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- Canonical SPDI
- NC_000022.11:28687960:C:T
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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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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
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. |
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CHEK2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4046 | 4101 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
Help
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 (1) |
criteria provided, single submitter
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Nov 5, 2023 | RCV000546521.11 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Nov 22, 2021 | RCV000572698.12 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 1, 2024 | RCV001569385.8 |
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
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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
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
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GeneKor MSA
Accession: SCV000821995.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Uncertain significance
(Sep 13, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002537396.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CHEK2 c.1568G>A (p.R523H) variant has been reported in an individual referred for hereditary cancer genetic testing (PMID: 31159747), and was also reported in healthy … (more)
The CHEK2 c.1568G>A (p.R523H) variant has been reported in an individual referred for hereditary cancer genetic testing (PMID: 31159747), and was also reported in healthy controls (PMID: 30287823). It was observed in 1/11734 chromosomes of the Finnish subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 460810). In silico tools suggest the impact of the variant on protein function is benign, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Aug 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004221732.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in an individual with a personal or family history of breast and/or ovarian cancer (PMID: 31159747 … (more)
In the published literature, this variant has been reported in an individual with a personal or family history of breast and/or ovarian cancer (PMID: 31159747 (2019)). However, this variant has also been reported in healthy individuals (PMIDs: 30287823 (2018), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2), FLOSSIES (https://whi.color.com)). The frequency of this variant in the general population, 0.0000086 (2/233408 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Nov 22, 2021)
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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: SCV001359171.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 523 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with histidine at codon 523 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with personal or family history of breast and/or ovarian cancer (PMID: 31159747). This variant has been identified in 2/233408 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
(Nov 05, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000633148.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 523 of the CHEK2 protein (p.Arg523His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 523 of the CHEK2 protein (p.Arg523His). 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 missense change has been observed in individual(s) with personal or family history of breast and/or ovarian cancer and pediatric neuroectodermal tumor (PMID: 31159747, 36468172). ClinVar contains an entry for this variant (Variation ID: 460810). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. (less)
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Likely benign
(Nov 13, 2018)
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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: SCV000669227.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Jul 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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GeneDx
Accession: SCV001793451.3
First in ClinVar: Aug 21, 2021 Last updated: Sep 16, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals referred for hereditary cancer genetic testing and in a pediatric patient with a primitive neuroectodermal tumor (PMID: 31159747, 36468172); This variant is associated with the following publications: (PMID: 30287823, 36468172, 36243179, 31159747) (less)
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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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The CHK2 kinase is recurrently mutated and functionally impaired in the germline of pediatric cancer patients. | Wagener R | International journal of cancer | 2023 | PMID: 36468172 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Text-mined citations for rs948928965 ...
HelpRecord 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.