ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1427C>A (p.Thr476Lys)
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.1427C>A (p.Thr476Lys)
Variation ID: 486833 Accession: VCV000486833.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28694066 (GRCh38) [ NCBI UCSC ] 22: 29090054 (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 Feb 19, 2018 Jun 17, 2024 Mar 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.1427C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Thr476Lys missense NM_001005735.2:c.1556C>A NP_001005735.1:p.Thr519Lys missense NM_001257387.2:c.764C>A NP_001244316.1:p.Thr255Lys missense NM_001349956.2:c.1226C>A NP_001336885.1:p.Thr409Lys missense NM_145862.2:c.1340C>A NP_665861.1:p.Thr447Lys missense NC_000022.11:g.28694066G>T NC_000022.10:g.29090054G>T NG_008150.2:g.52801C>A LRG_302:g.52801C>A LRG_302t1:c.1427C>A LRG_302p1:p.Thr476Lys - Protein change
- T476K, T255K, T447K, T409K, T519K
- Other names
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- Canonical SPDI
- NC_000022.11:28694065:G: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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 |
4047 | 4103 |
Conditions - Germline
Condition
Help
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
Help
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 (4) |
criteria provided, multiple submitters, no conflicts
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Aug 14, 2023 | RCV000570223.12 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 16, 2024 | RCV000698621.10 |
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
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000821993.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Uncertain significance
(May 19, 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: SCV002537373.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CHEK2 c.1427C>A (p.T476K) variant has been reported in at least 2 individuals with prostate or breast cancer, and in an individual with a personal/family … (more)
The CHEK2 c.1427C>A (p.T476K) variant has been reported in at least 2 individuals with prostate or breast cancer, and in an individual with a personal/family history suggestive of an inherite cancer condition (PMID: 12533788, 22419737, 31159747). It was not observed 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 486833). In silico tools suggest the impact of the variant on protein function is inconclusive, and functional studies have shown partially reduced CHEK2 kinase activity and an intermediate growth phenotype in a yeast-based complementation assay (PMID: 16835864, 22419737). 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
(Oct 19, 2022)
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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: SCV000827298.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 476 of the CHEK2 protein (p.Thr476Lys). … (more)
This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 476 of the CHEK2 protein (p.Thr476Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with prostate cancer (PMID: 16835864). ClinVar contains an entry for this variant (Variation ID: 486833). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CHEK2 function (PMID: 16835864, 22419737). 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
(Apr 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000689654.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with lysine at codon 476 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with lysine at codon 476 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). Functional studies demonstrated this variant had intermediate activity in a yeast DNA damage response assay (PMID: 22419737) but similar kinase activity to wild-type (PMID: 16835864). This variant has been observed in a prostate tumor sample (PMID: 16835864) and an individual referred for genetic testing (PMID: 31159747). This variant has not been identified 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
(Aug 14, 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: SCV000675997.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.T476K variant (also known as c.1427C>A), located in coding exon 12 of the CHEK2 gene, results from a C to A substitution at nucleotide … (more)
The p.T476K variant (also known as c.1427C>A), located in coding exon 12 of the CHEK2 gene, results from a C to A substitution at nucleotide position 1427. The threonine at codon 476 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). A yeast based complementation assay demonstrated that this alteration produced intermediate growth compared to wild-type and negative controls (Roeb, Higgens, and King. Hum. Mol. Genet. 2012 Jun; 21(12):2738-44). In addition, functional assays of CHEK2 kinase activity demonstrated that this alteration results in partially reduced activity (Wu X et al. Hum. Mutat. 2006 Aug; 27(8):742-7). This amino acid position is well 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
(Mar 16, 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: SCV005057505.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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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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Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Response to DNA damage of CHEK2 missense mutations in familial breast cancer. | Roeb W | Human molecular genetics | 2012 | PMID: 22419737 |
Unique substitution of CHEK2 and TP53 mutations implicated in primary prostate tumors and cancer cell lines. | Zheng L | Human mutation | 2006 | PMID: 16941491 |
Characterization of CHEK2 mutations in prostate cancer. | Wu X | Human mutation | 2006 | PMID: 16835864 |
Mutations in CHEK2 associated with prostate cancer risk. | Dong X | American journal of human genetics | 2003 | PMID: 12533788 |
Text-mined citations for rs142763740 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.