ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1053G>T (p.Glu351Asp)
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(8)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007194.4(CHEK2):c.1053G>T (p.Glu351Asp)
Variation ID: 142151 Accession: VCV000142151.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q12.1 22: 28696943 (GRCh38) [ NCBI UCSC ] 22: 29092931 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 19, 2017 Jun 17, 2024 Mar 6, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_007194.4:c.1053G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Glu351Asp missense NM_001005735.2:c.1182G>T NP_001005735.1:p.Glu394Asp missense NM_001257387.2:c.390G>T NP_001244316.1:p.Glu130Asp missense NM_001349956.2:c.852G>T NP_001336885.1:p.Glu284Asp missense NM_145862.2:c.1009-1070G>T intron variant NC_000022.11:g.28696943C>A NC_000022.10:g.29092931C>A NG_008150.2:g.49924G>T LRG_302:g.49924G>T LRG_302t1:c.1053G>T LRG_302p1:p.Glu351Asp - Protein change
- E351D, E394D, E130D, E284D
- Other names
- -
- Canonical SPDI
- NC_000022.11:28696942:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00009
Exome Aggregation Consortium (ExAC) 0.00013
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 |
3989 | 4043 |
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. |
---|---|---|---|---|
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 24, 2023 | RCV000131011.15 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 6, 2024 | RCV000456353.15 | |
Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
|
May 5, 2023 | RCV000481469.15 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Dec 21, 2018 | RCV001292666.3 | |
Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001354674.3 | |
not provided (1) |
no classification provided
|
- | RCV004556744.1 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821988.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
|
|
Uncertain significance
(Dec 21, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 2
Affected status: yes
Allele origin:
maternal
|
Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001481270.2 First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
Likely pathogenic
(Dec 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004221712.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMID: 32658311 (2021), 31159747 (2019)). A functional study indicates … (more)
In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMID: 32658311 (2021), 31159747 (2019)). A functional study indicates that this variant impacts protein function (PMID: 34903604 (2021)). 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 damaging. Based on the available information, this variant is classified as likely pathogenic. (less)
|
|
Uncertain significance
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000550478.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 351 of the CHEK2 … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 351 of the CHEK2 protein (p.Glu351Asp). This variant is present in population databases (rs587782268, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of CHEK2-related condtions (PMID: 31159747; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142151). 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. 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)
|
|
Uncertain significance
(Oct 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185937.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.E351D variant (also known as c.1053G>T), located in coding exon 9 of the CHEK2 gene, results from a G to T substitution at nucleotide … (more)
The p.E351D variant (also known as c.1053G>T), located in coding exon 9 of the CHEK2 gene, results from a G to T substitution at nucleotide position 1053. The glutamic acid at codon 351 is replaced by aspartic acid, an amino acid with highly similar properties. This variant has been identified in numerous disease cohorts as well as unaffected control groups across studies (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Decker B et al. J Med Genet, 2017 11;54:732-741; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Akcay IM et al. Int J Cancer, 2021 01;148:285-295; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration was reported as damaging in an mES cell-based assay of CHEK2 activity (Boonen RACM et al. Cancer Res, 2022 Feb;82:615-631). This alteration was also 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). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(Mar 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004217585.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
Uncertain significance
(May 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000565931.7
First in ClinVar: Apr 29, 2017 Last updated: May 13, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are conflicting: reduced kinase activity but auto-phosphorylation similar to wildtype (Boonen et al., 2021); Observed in individuals with a personal history of breast cancer, colorectal cancer, or other cancers in published literature (Tsaousis et al., 2019; Akcay et al., 2020; Decker et al., 2017; Zhang et al., 2015); Also known as c.1182G>T, p.(E394D); This variant is associated with the following publications: (PMID: 27149842, 21244692, 28423702, 31159747, elebi2022[article], 34903604, 19782031, 22419737, 36200007, 32658311, 28779002, 26580448) (less)
|
|
Uncertain significance
(Jul 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV003936130.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 351 of the CHEK2 … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 351 of the CHEK2 protein (p.Glu351Asp). This variant is present in population databases (rs587782268, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of CHEK2-related condtions (PMID: 27149842, 21244692, 28423702, 32658311, 34903604, 31159747, 19782031, 22419737). ClinVar contains an entry for this variant (Variation ID: 142151). In silico analysis supports that this missense variant has a deleterious effect on protein structure/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)
Age: 40-49 years
Sex: female
|
|
Uncertain significance
(Oct 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000684553.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with aspartic acid at codon 351 of the CHEK2 protein. Computational prediction suggests that this variant may not impact … (more)
This missense variant replaces glutamic acid with aspartic acid at codon 351 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). This variant has been reported as defective for phosphorylation of the CHEK2 substrate KAP1, but not CHEK2 threonine-183 autophosphorylation in a mouse embryonic stem cell based assay (PMID: 34903604). This variant has been reported in individuals affected with breast cancer and colorectal cancer (PMID: 32658311, 31159747). This variant has also been identified in 22/251292 chromosomes (18/30608 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). In a large breast cancer case-control study, this variant was observed in 10/60466 cases and 2/53461 unaffected controls; OR=4.421, 95%CI 0.969 to 20.18, p-value=0.043 (Leiden Open Variation Database DB-ID CHEK2_000058; PMID: 33471991). 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)
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549348.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The CHEK2 p.Glu351Asp variant was not identified in the literature nor was it identified in the MutDB or Zhejiang University databases. The variant was identified … (more)
The CHEK2 p.Glu351Asp variant was not identified in the literature nor was it identified in the MutDB or Zhejiang University databases. The variant was identified in dbSNP (ID: rs587782268) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx, and Color Genomics), Cosmic (2x in large intestine or endometrium tissue), and in LOVD 3.0 (1x likely benign). The variant was identified in control databases in 22 of 246082 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 4 of 111582 chromosomes (freq: 0.00004), and South Asian in 18 of 30780 chromosomes (freq: 0.0006), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Glu351 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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)
Number of individuals with the variant: 1
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952314.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807720.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001906398.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963590.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035344.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
CHEK2-related cancer predisposition
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749609.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Uncertain significance and reported on 11-05-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Uncertain significance and reported on 11-05-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Family history of cancer (present)
Indication for testing: Presymptomatic
Age: 70-79 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-11-05
Testing laboratory interpretation: Uncertain significance
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
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 |
Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk. | Boonen RACM | Cancer research | 2022 | PMID: 34903604 |
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls. | Akcay IM | International journal of cancer | 2021 | PMID: 32658311 |
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. | Decker B | Journal of medical genetics | 2017 | PMID: 28779002 |
Germline Mutations in Predisposition Genes in Pediatric Cancer. | Zhang J | The New England journal of medicine | 2015 | PMID: 26580448 |
Text-mined citations for rs587782268 ...
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.