ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.479T>C (p.Ile160Thr)
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.479T>C (p.Ile160Thr)
Variation ID: 186900 Accession: VCV000186900.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28725090 (GRCh38) [ NCBI UCSC ] 22: 29121078 (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 31, 2016 Jun 29, 2024 Mar 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.479T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Ile160Thr missense NM_001005735.2:c.608T>C NP_001005735.1:p.Ile203Thr missense NM_001257387.2:c.-299T>C 5 prime UTR NM_001349956.2:c.444+153T>C intron variant NM_145862.2:c.479T>C NP_665861.1:p.Ile160Thr missense NC_000022.11:g.28725090A>G NC_000022.10:g.29121078A>G NG_008150.2:g.21777T>C LRG_302:g.21777T>C LRG_302t1:c.479T>C LRG_302p1:p.Ile160Thr - Protein change
- I160T, I203T
- Other names
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- Canonical SPDI
- NC_000022.11:28725089:A:G
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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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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
4048 | 4104 |
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Sep 19, 2023 | RCV000166559.13 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Oct 30, 2023 | RCV000206788.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 11, 2020 | RCV000480734.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 20, 2024 | RCV001193681.6 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001356173.2 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
(Jun 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000689692.5
First in ClinVar: Feb 19, 2018 Last updated: Jan 08, 2022 |
Comment:
This missense variant replaces isoleucine with threonine at codon 160 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces isoleucine with threonine at codon 160 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown this variant to have damaging effect on CHEK2 protein function (PMID: 30851065). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251410 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
(Oct 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: SCV000489453.2
First in ClinVar: Jan 31, 2016 Last updated: Dec 24, 2022 |
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Uncertain significance
(Nov 11, 2020)
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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: SCV000567205.6
First in ClinVar: Apr 29, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect: large decrease in growth rate after DNA damage compared to wildtype (Delimitsou 2019); This variant is associated with the following publications: (PMID: 31398194, 30851065, 21153778) (less)
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Uncertain significance
(Mar 08, 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: SCV004020138.1
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 30, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000261388.10
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 160 of the CHEK2 protein (p.Ile160Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 160 of the CHEK2 protein (p.Ile160Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with prostate cancer (PMID: 32923906). This variant is also known as p.Ile203Thr. ClinVar contains an entry for this variant (Variation ID: 186900). 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). 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
(Sep 19, 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: SCV000217361.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.I160T variant (also known as c.479T>C), located in coding exon 3 of the CHEK2 gene, results from a T to C substitution at nucleotide … (more)
The p.I160T variant (also known as c.479T>C), located in coding exon 3 of the CHEK2 gene, results from a T to C substitution at nucleotide position 479. The isoleucine at codon 160 is replaced by threonine, an amino acid with similar properties. This variant was identified in 1/317 men in a metastatic prostate cancer cohort undergoing hereditary cancer genetic testing (Boyle JL et al. JCO Precis Oncol, 2020 Mar;4:). This alteration was also identified in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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) and was reported as damaging in an mES cell-based assay of CHEK2 activity (Boonen RACM et al. Cancer Res, 2022 02;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). Of note, this alteration is also known as c.608T>C in published literature. 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 20, 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: SCV001362693.5
First in ClinVar: Jun 22, 2020 Last updated: Jun 29, 2024 |
Comment:
Variant summary: CHEK2 c.479T>C (p.Ile160Thr) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Five … (more)
Variant summary: CHEK2 c.479T>C (p.Ile160Thr) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251410 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.479T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and Prostate Cancer, without evidence for causality. One publication reports experimental evidence indicating that the variant impairs DNA-damage repair in a yeast-based assay (Delimitsou_2019) and another indicates it is functionally impaired (Stolarova_2023), however additional evidence is needed to allow unequivocal conclusions about variant significance. The following publications have been ascertained in the context of this evaluation (PMID: 31398194, 32923906, 30851065, 21153778, 37449874). ClinVar contains an entry for this variant (Variation ID: 186900). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Familial ovarian cancer
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: SCV001551264.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The CHEK2 p.Ile160Thr variant was not identified in the literature. The variant was identified in dbSNP (ID: rs72552323) as "With Uncertain significance allele" and in … (more)
The CHEK2 p.Ile160Thr variant was not identified in the literature. The variant was identified in dbSNP (ID: rs72552323) as "With Uncertain significance allele" and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, Counsyl, GeneDx and Color). The variant was identified in control databases in 1 of 246208 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111664 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. Although the p.Ile160 residue is not conserved in mammals and other organisms, 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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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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 |
Pathogenic Germline DNA Repair Gene and HOXB13 Mutations in Men With Metastatic Prostate Cancer. | Boyle JL | JCO precision oncology | 2020 | PMID: 32923906 |
Computational analysis of high-risk SNPs in human CHK2 gene responsible for hereditary breast cancer: A functional and structural impact. | Badgujar NV | PloS one | 2019 | PMID: 31398194 |
Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. | Delimitsou A | Human mutation | 2019 | PMID: 30851065 |
Prioritization of candidate SNPs in colon cancer using bioinformatics tools: an alternative approach for a cancer biologist. | George Priya Doss C | Interdisciplinary sciences, computational life sciences | 2010 | PMID: 21153778 |
Text-mined citations for rs72552323 ...
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.