ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1180G>A (p.Glu394Lys)
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.
Likely pathogenic(1); Uncertain significance(9)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007194.4(CHEK2):c.1180G>A (p.Glu394Lys)
Variation ID: 128048 Accession: VCV000128048.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28695789 (GRCh38) [ NCBI UCSC ] 22: 29091777 (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 Jan 7, 2017 May 1, 2024 Dec 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.1180G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Glu394Lys missense NM_001005735.2:c.1309G>A NP_001005735.1:p.Glu437Lys missense NM_001257387.2:c.517G>A NP_001244316.1:p.Glu173Lys missense NM_001349956.2:c.979G>A NP_001336885.1:p.Glu327Lys missense NM_145862.2:c.1093G>A NP_665861.1:p.Glu365Lys missense NC_000022.11:g.28695789C>T NC_000022.10:g.29091777C>T NG_008150.2:g.51078G>A LRG_302:g.51078G>A LRG_302t1:c.1180G>A LRG_302p1:p.Glu394Lys - Protein change
- E394K, E327K, E173K, E365K, E437K
- Other names
- p.E394K:GAA>AAA
- Canonical SPDI
- NC_000022.11:28695788: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
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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 |
4004 | 4059 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Dec 28, 2023 | RCV000115986.18 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2023 | RCV000228584.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 24, 2021 | RCV000212453.6 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001356701.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 19, 2023 | RCV003483480.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 21, 2023 | RCV003226200.1 |
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
(Oct 14, 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: SCV002537028.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CHEK2 c.1180G>A (p.E394K) variant has been reported in multiple individuals with breast cancer (PMID: 30303537, 31050813, 31784482, 31409080). Additionally, a large case-control study reported … (more)
The CHEK2 c.1180G>A (p.E394K) variant has been reported in multiple individuals with breast cancer (PMID: 30303537, 31050813, 31784482, 31409080). Additionally, a large case-control study reported the variant in 2/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). It was observed in 2/10076 chromosomes of the Ashkenazi Jewish 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 128048). In silico tools suggest the impact of the variant on protein function is deleterious. Functional studies showed that the variant impairs CHEK2 kinase activity and renders yeast cells to be sensitive to DNA damage (PMID: 30851065, 31050813). 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
(May 24, 2021)
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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: SCV000149895.15
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious … (more)
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate damaging effects: Reduced kinase activity and DNA damage response (Delimitsou 2019, Kleiblova 2019); Observed in an individual with breast cancer (Kleiblova 2019); This variant is associated with the following publications: (PMID: 18571837, 24573554, 22578220, 23856246, 21765476, 30851065, 31050813, 30303537, 31398194) (less)
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Uncertain significance
(Mar 21, 2023)
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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: SCV003923011.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: CHEK2 c.1180G>A (p.Glu394Lys) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four … (more)
Variant summary: CHEK2 c.1180G>A (p.Glu394Lys) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251066 control chromosomes. c.1180G>A has been reported in the literature as a VUS in settings of multigene panel testing and in case control studies of individuals affected with breast cancer (example, Doddato_2021, Girard_2019, Bora_2022, Kleibova_2019). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in in-vivo characterization as damaging in a yeast functional assay evaluating ability to repair methylmethanesulfonate (MMS) induced DNA damage (example, Delimitsou_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(May 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV003927254.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
a variant of uncertain significance in the CHEK2 gene. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic … (more)
a variant of uncertain significance in the CHEK2 gene. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 394 of the CHEK2 protein (p.Glu394Lys). This variant is present in population databases (rs587780169, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 30303537, 31050813, 31784482). ClinVar contains an entry for this variant (Variation ID: 128048).this alteration is predicted to be pathogenic computational verdict based on 20 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL , SIFT , CADD, MutPred , LRT , SIFT4G , REVEL , MetaRNN and Polyphen2 vs non benign prediction. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 30851065, 31409080). 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. pathogenic/likely pathogenic variants in the CHEK2 gene cause autosomal dominant susceptibility to breast cancer (OMIM 114480). (less)
Age: 50-59 years
Sex: female
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Uncertain significance
(Oct 16, 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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Baylor Genetics
Accession: SCV004217506.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Aug 01, 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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Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV004228004.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
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Likely pathogenic
(Dec 19, 2023)
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criteria provided, single submitter
Method: curation
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Hereditary breast ovarian cancer syndrome
Affected status: not provided
Allele origin:
germline
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German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV004228278.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
. According to the ACMG standard criteria we chose these criteria: PS3 (strong pathogenic): Deleterious in : Stolarova et al 2023 (PMID: 37449874), Kleiblova et … (more)
. According to the ACMG standard criteria we chose these criteria: PS3 (strong pathogenic): Deleterious in : Stolarova et al 2023 (PMID: 37449874), Kleiblova et al 2019 (PMID: 31050813), Delimitsou et al 2019 (PMID: 30851065), PM2 (supporting pathogenic): popmax: AFR popmax AF:2.41220e-05, PP3 (supporting pathogenic): REVEL: 0.864, BayesDEL:0.394329 (less)
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Uncertain significance
(Dec 19, 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: SCV000289650.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 394 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 394 of the CHEK2 protein (p.Glu394Lys). This variant is present in population databases (rs587780169, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 30303537, 31050813, 31784482, 35220195). This variant is also known as c.1309G>A (p.Glu437Lys). ClinVar contains an entry for this variant (Variation ID: 128048). 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 disruptive. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 30851065, 31409080). 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
(Dec 28, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000684565.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with lysine at codon 394 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces glutamic acid with lysine at codon 394 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown this variant to be damaging to protein function in in vitro and cell based kinase assays (PMID: 31050813, 33606978) and in a DNA damage repair assay in yeast (PMID: 30851065). This variant has been reported in one individual each affected with breast cancer (PMID: 31050813), prostate cancer (PMID: 37842866) and breast, ovarian or pancreatic cancer (PMID: 34026625). This variant also has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000345). This variant has been identified in 5/251066 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
(Dec 07, 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: SCV000184403.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.E394K variant (also known as c.1180G>A), located in coding exon 10 of the CHEK2 gene, results from a G to A substitution at nucleotide … (more)
The p.E394K variant (also known as c.1180G>A), located in coding exon 10 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1180. The glutamic acid at codon 394 is replaced by lysine, an amino acid with similar properties. This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). Additionally, this alteration was identified in 1/1928 breast and/or ovarian cancer patients and 0/3360 population-matched controls. In a functional assay included in this study, this variant was reported as non-functional in both in vitro kinase and human-cell based assays of KAP1 phosphorylation (Kleiblova P et al. Int. J. Cancer, 2019 Oct;145:1782-1797). This alteration was reported as functionally impaired in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). Finally, this variant demonstrated enrichment behavior in the presence of doxorubicin and olaparib and reduced expression of CHK2 in a drug sensitivity assay performed in MCF10A -BE3 cells with CRISPR-introduced variants (Cuella-Martin R et al. Cell, 2021 Feb;184:1081-1097.e19). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551942.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The CHEK2 p.Glu394Lys variant was not identified in the literature nor was it identified in the MutDB, or Zhejiang Colon Cancer Database. The variant was … (more)
The CHEK2 p.Glu394Lys variant was not identified in the literature nor was it identified in the MutDB, or Zhejiang Colon Cancer Database. The variant was also identified in the following databases: dbSNP (ID: rs587780169) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Ambry Genetics and Invitae), Clinvitae (3x), Cosmic (2x in a malignant melanoma and lymphoid neoplasm), and in control databases in 5 of 245908 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Observations by population include European Non-Finnish in 3 of 111386 chromosomes (freq: 0.00003), and Ashkenazi Jewish in 2 of 9846 chromosomes (freq: 0.0002); it was not observed in the African, “Other”, Latino, East Asian, European Finnish, and South Asian populations. The p.Glu394 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Lys variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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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Whole exome germline sequencing in early-onset prostate cancer patients: Genomic findings and clinical outcomes. | Siegelmann-Danieli N | The Prostate | 2024 | PMID: 37842866 |
ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk. | Stolarova L | Clinical cancer research : an official journal of the American Association for Cancer Research | 2023 | PMID: 37449874 |
Evaluation of hereditary/familial breast cancer patients with multigene targeted next generation sequencing panel and MLPA analysis in Turkey. | Bora E | Cancer genetics | 2022 | PMID: 35220195 |
Exome sequencing in BRCA1-2 candidate familias: the contribution of other cancer susceptibility genes. | Doddato G | Frontiers in oncology | 2021 | PMID: 34026625 |
Functional interrogation of DNA damage response variants with base editing screens. | Cuella-Martin R | Cell | 2021 | PMID: 33606978 |
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 |
Retesting of women who are negative for a BRCA1 and BRCA2 mutation using a 20-gene panel. | Lerner-Ellis J | Journal of medical genetics | 2020 | PMID: 31784482 |
Germline CHEK2 Gene Mutations in Hereditary Breast Cancer Predisposition - Mutation Types and their Biological and Clinical Relevance. | Kleiblová P | Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti | 2019 | PMID: 31409080 |
Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. | Kleiblova P | International journal of cancer | 2019 | PMID: 31050813 |
Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. | Delimitsou A | Human mutation | 2019 | PMID: 30851065 |
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 |
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Text-mined citations for rs587780169 ...
HelpRecord last updated Jul 15, 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.