ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1133C>T (p.Thr378Ile)
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.1133C>T (p.Thr378Ile)
Variation ID: 128046 Accession: VCV000128046.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28695836 (GRCh38) [ NCBI UCSC ] 22: 29091824 (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 Oct 8, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.1133C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Thr378Ile missense NM_001005735.2:c.1262C>T NP_001005735.1:p.Thr421Ile missense NM_001257387.2:c.470C>T NP_001244316.1:p.Thr157Ile missense NM_001349956.2:c.932C>T NP_001336885.1:p.Thr311Ile missense NM_145862.2:c.1046C>T NP_665861.1:p.Thr349Ile missense NC_000022.11:g.28695836G>A NC_000022.10:g.29091824G>A NG_008150.2:g.51031C>T LRG_302:g.51031C>T LRG_302t1:c.1133C>T LRG_302p1:p.Thr378Ile - Protein change
- T378I, T157I, T311I, T349I, T421I
- Other names
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p.T378I:ACC>ATC
- Canonical SPDI
- NC_000022.11:28695835:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00007
- Links
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 |
4053 | 4109 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jul 20, 2023 | RCV000115984.21 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2024 | RCV000231285.19 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Feb 11, 2024 | RCV000656835.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000764376.6 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2024 | RCV001420894.11 | |
CHEK2-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Mar 13, 2024 | RCV004529940.2 |
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
(Sep 29, 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: SCV004217531.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Jul 20, 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: SCV000186773.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.T378I variant (also known as c.1133C>T), located in coding exon 10 of the CHEK2 gene, results from a C to T substitution at nucleotide … (more)
The p.T378I variant (also known as c.1133C>T), located in coding exon 10 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1133. The threonine at codon 378 is replaced by isoleucine, an amino acid with similar properties. 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 well 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)
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Uncertain significance
(Aug 21, 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: SCV002537025.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CHEK2 c.1133C>T (p.T378I) variant has been reported in heterozygosity in individuals with breast cancer as well as healthy controls (PMID: 33471991). An in vivo … (more)
The CHEK2 c.1133C>T (p.T378I) variant has been reported in heterozygosity in individuals with breast cancer as well as healthy controls (PMID: 33471991). An in vivo yeast-based study demonstrated the normal function of the protein (PMID:30851065). This variant was observed in 13/250714 chromosomes in the large and broad populations of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 128046). 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
(Jan 24, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000289645.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 378 of the CHEK2 protein (p.Thr378Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 378 of the CHEK2 protein (p.Thr378Ile). This variant is present in population databases (rs587780167, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 34282249). ClinVar contains an entry for this variant (Variation ID: 128046). 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 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
(Dec 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000537537.6
First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with isoleucine at codon 378 in the kinase domain of the CHEK2 protein. The reference threonine residue has been shown … (more)
This missense variant replaces threonine with isoleucine at codon 378 in the kinase domain of the CHEK2 protein. The reference threonine residue has been shown to be phosphorylated in response to DNA damage stimuli (PMID: 17698850, 20713355) and to play a role in regulating ionizing radiation-induced kinase activity (PMID: 20713355). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown the mutant protein to be functional in DNA damage repair assay in yeast (PMID: 30851065). In a large breast cancer case-control study, this variant was observed in 9/60466 cases and 7/53461 unaffected controls (OR=1.137, 95%CI 0.423 to 3.053, p-value=1) (PMID: 33471991, Leiden Open Variation Database DB-ID CHEK2_000355). This variant has been identified in 13/250714 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
(Jul 31, 2024)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002761100.5
First in ClinVar: Dec 17, 2022 Last updated: Aug 04, 2024 |
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Uncertain significance
(Jun 24, 2024)
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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: SCV001623332.3
First in ClinVar: May 23, 2021 Last updated: Sep 16, 2024 |
Comment:
Variant summary: CHEK2 c.1133C>T (p.Thr378Ile) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three … (more)
Variant summary: CHEK2 c.1133C>T (p.Thr378Ile) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250714 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (5.2e-05 vs 0.00031), allowing no conclusion about variant significance. c.1133C>T has been reported in the literature in unaffected controls and individuals with breast cancer (example, Weitzel_2019, Dorling_2021/LOVD database, Stolarova_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been reported (BRIP1 c.2108delinsTCC, p.Lys703Ilefs*3 in Helgadottir_2021), providing supporting evidence for a benign role. In a functional study, the variant results in reduced KAP1 phosphorylation and CHK2 autophosphorylation activity (35.8% and 47.5% versus wild type, respectively) in vitro in a human CHEK2-knockout background (example, Stolarova_2023). A further study showed no damaging effect of this variant in an in vivo yeast based assay comparing growth rates of each strain with positive and negative controls, however the relevance of this assay with respect to CHEK2 function in humans is unclear (example, Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30851065, 33471991, 34282249, 37449874, 31206626). ClinVar contains an entry for this variant (Variation ID: 128046). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Familial prostate cancer Bone osteosarcoma Li-Fraumeni syndrome 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000895411.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(May 05, 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: SCV000488585.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 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: SCV004020172.1
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
(Oct 04, 2022)
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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: SCV000601144.4
First in ClinVar: Oct 09, 2016 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.00012 (4/34568 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant has been reported … (more)
The frequency of this variant in the general population, 0.00012 (4/34568 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant has been reported in individuals affected with breast cancer and unaffected controls (PMIDs: 30851065 (2019) and 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). A yeast-based functional study has indicated that this variant maintains CHEK2 protein function (PMID: 30851065 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Dec 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197498.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Uncertain significance
(Feb 11, 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: SCV000149893.16
First in ClinVar: May 17, 2014 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate DNA damage response and cell growth comparable to wild type in yeast-based assays but impaired kinase activity and auto-phosphorylation in human-cell … (more)
Published functional studies demonstrate DNA damage response and cell growth comparable to wild type in yeast-based assays but impaired kinase activity and auto-phosphorylation in human-cell based studies (PMID: 30851065, 37449874); Observed in individuals with breast cancer and in unaffected controls (PMID: 31206626, 33471991, 34282249, 37449874); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33471991, 30851065, 31206626, 34282249, 37449874, 22419737, 19782031, 20713355, 17698850) (less)
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Uncertain significance
(Mar 13, 2024)
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no assertion criteria provided
Method: clinical testing
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CHEK2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004729311.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The CHEK2 c.1133C>T variant is predicted to result in the amino acid substitution p.Thr378Ile. This variant was reported in an individual with breast cancer in … (more)
The CHEK2 c.1133C>T variant is predicted to result in the amino acid substitution p.Thr378Ile. This variant was reported in an individual with breast cancer in the presence of a pathogenic variant in a different gene (Helgadottir et al. 2021. PubMed ID: 34282249). However, this variant has also been documented in controls (Table S3, Weitzel et al. 2019. PubMed ID: 31206626). An in vivo, yeast-based growth rate assay showed this variant behaved similar to wild type CHEK2 (Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations in ClinVar of likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128046/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (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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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 |
Sequencing for germline mutations in Swedish breast cancer families reveals novel breast cancer risk genes. | Helgadottir HT | Scientific reports | 2021 | PMID: 34282249 |
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 |
Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer. | Weitzel JN | Cancer | 2019 | PMID: 31206626 |
Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. | Delimitsou A | Human mutation | 2019 | PMID: 30851065 |
Interdependent phosphorylation within the kinase domain T-loop Regulates CHK2 activity. | Guo X | The Journal of biological chemistry | 2010 | PMID: 20713355 |
Human T-cell leukemia virus type 1 Tax oncoprotein prevents DNA damage-induced chromatin egress of hyperphosphorylated Chk2. | Gupta SK | The Journal of biological chemistry | 2007 | PMID: 17698850 |
Text-mined citations for rs587780167 ...
HelpRecord last updated Nov 25, 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.