ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1582G>A (p.Glu528Lys)
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.1582G>A (p.Glu528Lys)
Variation ID: 142361 Accession: VCV000142361.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28687947 (GRCh38) [ NCBI UCSC ] 22: 29083935 (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 Jul 1, 2016 Jun 17, 2024 Feb 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.1582G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Glu528Lys missense NM_001005735.2:c.1711G>A NP_001005735.1:p.Glu571Lys missense NM_001257387.2:c.919G>A NP_001244316.1:p.Glu307Lys missense NM_001349956.2:c.1381G>A NP_001336885.1:p.Glu461Lys missense NM_145862.2:c.1495G>A NP_665861.1:p.Glu499Lys missense NC_000022.11:g.28687947C>T NC_000022.10:g.29083935C>T NG_008150.2:g.58920G>A LRG_302:g.58920G>A LRG_302t1:c.1582G>A LRG_302p1:p.Glu528Lys - Protein change
- E528K, E571K, E307K, E461K, E499K
- Other names
- p.E528K:GAG>AAG
- Canonical SPDI
- NC_000022.11:28687946: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00014
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 |
4045 | 4100 |
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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Oct 21, 2022 | RCV000131443.18 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Feb 17, 2024 | RCV000233973.19 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 23, 2023 | RCV000588204.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 5, 2021 | RCV001290447.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 14, 2022 | RCV002492512.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV004556747.1 |
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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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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CHEK2-Related Cancer Susceptibility
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001307872.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Dec 17, 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: SCV002537399.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CHEK2 c.1582G>A (p.E528K) variant has been reported in heterozygosity in at least 2 individuals with colorectal cancer and diffuse large B cell lymphoma (PMID: … (more)
The CHEK2 c.1582G>A (p.E528K) variant has been reported in heterozygosity in at least 2 individuals with colorectal cancer and diffuse large B cell lymphoma (PMID: 28135145, 23960188). This variant has also been reported in at least three individuals with breast cancer and two unaffected controls in a large case-control study (PMID:33471991). A research study demonstrated the variant does not affect the growth of yeast cells (PMID: 30851065). This variant was observed in 2/19558 chromosomes in the East Asian 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: 142361). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. 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 23, 2023)
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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: SCV000210999.14
First in ClinVar: Feb 24, 2015 Last updated: Aug 31, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports 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 supports that this missense variant does not alter protein structure/function; Observed in individuals with colon cancer and lymphoma (de Miranda et al., 2013; Yurgelun et al., 2017); Published functional studies demonstrate no damaging effect: cell growth and proliferation after DNA damage similar to wild type (Delimitsou et al., 2019); This variant is associated with the following publications: (PMID: 23960188, 28135145, 28211887, 31398194, 32906215, 30851065) (less)
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Uncertain significance
(Feb 17, 2024)
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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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Baylor Genetics
Accession: SCV004217595.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(Jan 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698787.2
First in ClinVar: Mar 17, 2018 Last updated: Feb 12, 2021 |
Comment:
Variant summary: CHEK2 c.1582G>A (p.Glu528Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: CHEK2 c.1582G>A (p.Glu528Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 233632 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1582G>A has been reported in the literature as a germline variant in individuals with diffuse large B-cell lymphoma (DLBCL) and colorectal cancer (e.g. deMiranda_2013, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant showed no damaging effects in a yeast-based assay (e.g. Delimitsou_2019). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(May 03, 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: SCV000684611.4
First in ClinVar: Feb 19, 2018 Last updated: Jan 08, 2022 |
Comment:
This missense variant replaces glutamic acid with lysine at codon 528 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces glutamic acid with lysine at codon 528 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. An experimental functional study has been shown this variant to be neutral in a yeast based DNA damage repair assay (PMID: 30851065). This variant has been reported in individuals affected with colorectal cancer in the literature (PMID: 28135145). This variant has been identified in 8/265030 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
(Sep 29, 2016)
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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: SCV000489379.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
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Uncertain significance
(Feb 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Colorectal cancer Familial prostate cancer Bone osteosarcoma Li-Fraumeni syndrome 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002792421.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Mar 09, 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:
unknown
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Myriad Genetics, Inc.
Accession: SCV004020216.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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Uncertain significance
(Jan 31, 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: SCV001470306.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
Comment:
In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 28135145 (2017)). A yeast functional assay found that this … (more)
In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 28135145 (2017)). A yeast functional assay found that this variant had a benign effect on protein function (PMID: 30851065 (2019)). The frequency of this variant in the general population, 0.00004 (5/124096 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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
(Jan 03, 2024)
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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: SCV000289672.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 528 of the CHEK2 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 528 of the CHEK2 protein (p.Glu528Lys). 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 diffuse large B cell lymphoma and colorectal cancer (PMID: 23960188, 28135145, 34326862). ClinVar contains an entry for this variant (Variation ID: 142361). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065). 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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Uncertain significance
(Oct 21, 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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Ambry Genetics
Accession: SCV000186427.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.E528K variant (also known as c.1582G>A), located in coding exon 14 of the CHEK2 gene, results from a G to A substitution at nucleotide … (more)
The p.E528K variant (also known as c.1582G>A), located in coding exon 14 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1582. The glutamic acid at codon 528 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in the germline of one Chinese individual diagnosed with diffuse large B-cell lymphoma (de Miranda NF et al. J. Exp. Med. 2013 Aug;210:1729-42). In addition, this alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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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CHEK2 variants: linking functional impact to cancer risk. | Boonen RACM | Trends in cancer | 2022 | PMID: 35643632 |
Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. | Bhai P | Frontiers in genetics | 2021 | PMID: 34326862 |
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 |
Comprehensive analysis and ACMG-based classification of CHEK2 variants in hereditary cancer patients. | Vargas-Parra G | Human mutation | 2020 | PMID: 32906215 |
Computational analysis of high-risk SNPs in human CHK2 gene responsible for hereditary breast cancer: A functional and structural impact. | Badgujar NV | PloS one | 2019 | PMID: 31398194 |
Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. | Delimitsou A | Human mutation | 2019 | PMID: 30851065 |
Germline mutations predisposing to diffuse large B-cell lymphoma. | Leeksma OC | Blood cancer journal | 2017 | PMID: 28211887 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
DNA repair genes are selectively mutated in diffuse large B cell lymphomas. | de Miranda NF | The Journal of experimental medicine | 2013 | PMID: 23960188 |
Text-mined citations for rs138040612 ...
HelpRecord last updated Sep 01, 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.