ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.320-5T>A
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.
Uncertain significance(5); Benign(3); Likely benign(10)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007194.4(CHEK2):c.320-5T>A
Variation ID: 128070 Accession: VCV000128070.61
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28725372 (GRCh38) [ NCBI UCSC ] 22: 29121360 (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 Jun 4, 2014 May 1, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.320-5T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001005735.2:c.449-5T>A intron variant NM_001257387.2:c.-458-5T>A intron variant NM_001349956.2:c.320-5T>A intron variant NM_145862.2:c.320-5T>A intron variant NC_000022.11:g.28725372A>T NC_000022.10:g.29121360A>T NG_008150.2:g.21495T>A LRG_302:g.21495T>A LRG_302t1:c.320-5T>A - Protein change
- Other names
- IVS2-5T>A
- chr22:29,121,360A>T
- Canonical SPDI
- NC_000022.11:28725371:A: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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0.00080 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
Exome Aggregation Consortium (ExAC) 0.00052
The Genome Aggregation Database (gnomAD), exomes 0.00057
The Genome Aggregation Database (gnomAD) 0.00070
1000 Genomes Project 0.00080
1000 Genomes Project 30x 0.00094
Trans-Omics for Precision Medicine (TOPMed) 0.00126
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 | ||
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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. |
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CHEK2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3983 | 4037 |
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. |
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Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Jul 21, 2021 | RCV000116011.21 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Oct 1, 2022 | RCV000119289.41 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000195943.29 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000212412.22 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000779369.12 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 1, 2019 | RCV001171460.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2023 | RCV001798354.11 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 23, 2024 | RCV003492504.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV003891616.1 |
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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Benign
(Apr 11, 2019)
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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: SCV000698794.2
First in ClinVar: Jun 04, 2014 Last updated: Nov 08, 2019 |
Comment:
Variant summary: CHEK2 c.320-5T>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: CHEK2 c.320-5T>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict the variant slightly weakens a 3 acceptor site. An in silico analysis also predicted the variant to result in a reduced splicing efficiency that could activate pre-existing cryptic acceptor 92 nucleotide upstream of the natural site, leading to the inclusion of 92 nucleotide of the intron. However this effect was predicted to be partial, with the variant mRNA relatively less abundant compared to the wild type (Mucaki 2016). Two publications reported experimental evidence evaluating splicing impact: one identified an in frame transcript variant lacking exon 3 and 4, however, the amount of the shortened transcript compared to wild type was less than 20%, suggesting that this variant reduces but does not eliminate the usage of the consensus splice acceptor and can therefore be regarded as a hypomorphic allele (Kraus 2017); whereas the other study reported splice analysis from 2 patients showing no significant change in RNA splicing, however without providing experimental evidence (Tsai 2018). The variant allele was found at a frequency of 0.00053 in 288862 control chromosomes (gnomAD and publication data), including 1 homozygote. The observed variant frequency is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Breast Cancer phenotype (0.00031), strongly suggesting that the variant is benign. In addition, this variant has been reported in 10/9884 American women who are older than age 70 and cancer free (FLOSSIES database). c.320-5T>A has been reported in the literature in individuals affected with various tumor phenotypes, including breast-/ovarian-, colorectal- and pancreas cancer, non-Hodgkin lymphoma and Lynch syndrome (Kleibl 2008, Kleibl 2009, Mohelnikova-Duchonova 2010, Havranek 2015, Castera 2014, Tung 2015, Yurgelun 2015, Kraus 2017, Decker 2017, Bonache 2018, Hampel 2018). These reports however do not provide unequivocal conclusions about association of the variant with Breast Cancer. In addition, in two of these patients co-occurrences with other pathogenic variants have been reported (CHEK2 exon 2 deletion, Tung 2015; MLH1 c.1381A>T/K461X, Hampel 2018), providing supporting evidence for a benign role. Though one case-control study suggested that the variant might be associated with breast cancer, the carrier frequency in healthy controls recruited in this study was much lower than observed in population datasets, therefore this postulation might be the result of sampling error (Decker 2017). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (6 calling it a VUS, 2 classifying as likely benign, and 1 as benign). Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Jan 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002070850.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Benign
(Dec 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601165.4
First in ClinVar: Sep 28, 2017 Last updated: Dec 31, 2022 |
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Benign
(Feb 01, 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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Invitae
Accession: SCV000253484.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
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Likely benign
(Mar 28, 2018)
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criteria provided, single submitter
Method: research
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Hereditary Breast Carcinoma
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
germline
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000611874.2
First in ClinVar: Apr 16, 2017 Last updated: Feb 23, 2019 |
Comment:
The CHEK2 variant designated as NM_007194.3:c.320-5T>A is classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, … (more)
The CHEK2 variant designated as NM_007194.3:c.320-5T>A is classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 1.38 to 1 (Thompson, et al., 2003, PMID:12900794). This likelihood ratio indicates weak evidence that the allele co-segregates disease in this family. However, RNA studies in two individuals unrelated from different families show no significant change in RNA splicing or protein transcripts, thus providing strong evidence that this variant does not alter the CHEK2 protein. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 128070). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter CHEK2 function or modify cancer risk. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. (less)
Family history: yes
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Likely benign
(May 13, 2016)
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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: SCV000902592.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Uncertain significance
(Jul 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603086.2
First in ClinVar: Sep 28, 2017 Last updated: Jan 26, 2021 |
Comment:
The CHEK2 c.320-5T>A variant has been described in the literature in individuals affected with different cancers, including breast and/or ovarian cancer, Hodgkin lymphoma, and colorectal … (more)
The CHEK2 c.320-5T>A variant has been described in the literature in individuals affected with different cancers, including breast and/or ovarian cancer, Hodgkin lymphoma, and colorectal cancer (Castera 2014, Hampel 2018, Havranek 2011, Kleibl 2008, Kleibl 2009, Kraus 2017, Tung 2015). However, several affected individuals with this variant were found to carry an additional pathogenic variant (Hampel 2018, Tung 2015). The c.320-5T>A variant is found in the general population with an overall allele frequency of 0.05% (152/282198 alleles, including one homozygote) in the Genome Aggregation Database, including an increased frequency of 0.37% (38/10362 alleles) in the Ashkenazi Jewish population. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. Functional analyses of patient RNAs show exon skipping in a small minority of transcripts (Casadei 2019, Kraus 2017); however, it is unclear that these splicing alterations are clinically significant. While existing evidence suggests this variant is unlikely to cause disease in all carriers, given the possibility of a low penetrance effect, the clinical significance of the c.320-5T>A variant is uncertain at this time. References: Casadei S et al. Characterization of splice-altering mutations in inherited predisposition to cancer. Proc Natl Acad Sci U S A. 2019;116(52):26798-26807. Castera L et al. Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum Genet. 2014 Nov;22(11):1305-13. Hampel H et al. Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer. JAMA Oncol. 2018;4(6):806-813. Havranek O et al. Alterations of CHEK2 forkhead-associated domain increase the risk of Hodgkin lymphoma. Neoplasma. 2011;58(5):392-5. Kleibl Z et al. Analysis of CHEK2 FHA domain in Czech patients with sporadic breast cancer revealed distinct rare genetic alterations. Breast Cancer Res Treat. 2008 Nov;112(1):159-64. Kleibl Z et al. The CHEK2 gene I157T mutation and other alterations in its proximity increase the risk of sporadic colorectal cancer in the Czech population. Eur J Cancer. 2009 Mar;45(4):618-24. Kraus C et al. Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Int J Cancer. 2017;140(1):95-102. Mucaki EJ et al. A unified analytic framework for prioritization of non-coding variants of uncertain significance in heritable breast and ovarian cancer. BMC Med Genomics. 2016 Apr 11;9:19. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015;121(1):25-33. (less)
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Likely benign
(May 19, 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: SCV000149920.14
First in ClinVar: May 17, 2014 Last updated: Jun 04, 2014 |
Comment:
Patient RNA studies demonstrate aberrant splicing resulting in an in-frame transcript lacking exons 3 and 4 present at approximately 20%, as well as full-length transcript … (more)
Patient RNA studies demonstrate aberrant splicing resulting in an in-frame transcript lacking exons 3 and 4 present at approximately 20%, as well as full-length transcript (Kraus 2017, Vargas-Parra 2020); In-silico analysis is inconclusive as to whether the variant alters gene splicing; Also known as IVS1-5T>A; This variant is associated with the following publications: (PMID: 18058223, 20643596, 21744992, 25980754, 24549055, 18996005, 27067391, 27616075, 27621404, 26506619, 29596542, 25186627, 30306255, 31422574, 28779002, 30374176, 29337092, 32906215) (less)
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Likely benign
(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: SCV004020194.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
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Likely benign
(Aug 15, 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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002761116.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
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Uncertain significance
(Apr 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002043401.2
First in ClinVar: Jan 01, 2022 Last updated: Feb 04, 2024 |
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Uncertain significance
(Dec 06, 2023)
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criteria provided, single submitter
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: SCV000806878.2
First in ClinVar: Sep 13, 2018 Last updated: Mar 16, 2024 |
Comment:
The CHEK2 c.320-5T>A variant is predicted to interfere with splicing. This variant has been reported in individuals with breast and colorectal cancer and Hodgkin lymphoma … (more)
The CHEK2 c.320-5T>A variant is predicted to interfere with splicing. This variant has been reported in individuals with breast and colorectal cancer and Hodgkin lymphoma (Kleibl et al. 2008. PubMed ID: 18058223; Kleibl et al. 2009. PubMed ID: 18996005; Havranek et al. 2011. PubMed ID: 21744992). RNA studies on blood from a patient carrying this variant identified a novel CHEK2 transcript with in-frame omission of exons 3 and 4. However, this transcript was detected at a level <20% of normal, prompting the authors to conclude it may be a hypomorphic allele (Kraus et al. 2017. PubMed ID: 27616075). This variant is reported in 0.37% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant has also been reported in ClinVar with conflicting interpretations from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128070/). 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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Uncertain significance
(Apr 26, 2018)
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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: SCV000786412.2
First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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CHEK2-Related Cancer Susceptibility
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915970.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The CHEK2 c.320-5T>A splice region variant has been reported in a heterozygous state in at least five individuals with various cancers (Kleibl et al. 2008; … (more)
The CHEK2 c.320-5T>A splice region variant has been reported in a heterozygous state in at least five individuals with various cancers (Kleibl et al. 2008; Kleibl et al. 2009; Mohelnikova-Duchonova et al. 2010; Havranek et al. 2011; Kraus et al. 2016; Mucaki et al. 2016). Of these five individuals, the variant was found in one patient with sporadic breast cancer, one with colorectal cancer, one with sporadic pancreatic cancer, one with Hodgkin lymphoma, and one with hereditary breast or ovarian cancer. The c.320-5T>A variant was absent from 1366 control chromosomes (Kleibl et al. 2008), but is reported at a frequency of 0.01402 in the Iberian population in Spain from the 1000 Genomes Project. Kraus et al. (2016) demonstrated using RT-PCR analysis that the c.320-5T>A variant resulted in an in-frame transcript lacking exons 3 and 4 that was stably expressed, however at low levels (about 20%) compared to the level of wild type transcript, suggesting a leaky splicing defect and a hypomorphic allele. Based on the evidence, the c.320-5T>A variant is classified as a variant of unknown significance but suspicious for pathogenicity for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely benign
(Jul 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: SCV002537418.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Jan 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000839498.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 04, 2024 |
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Likely benign
(Oct 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245717.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
CHEK2: BP4, BS1:Supporting, BS2
Number of individuals with the variant: 5
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Likely benign
(Nov 08, 2018)
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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: SCV000172844.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Pathogenic
(Sep 01, 2019)
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no assertion criteria provided
Method: research
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Familial cancer of breast
Li-Fraumeni syndrome 2
Affected status: yes
Allele origin:
germline
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King Laboratory, University of Washington
Accession: SCV001251371.1
First in ClinVar: Jun 07, 2020 Last updated: Jun 07, 2020
Comment:
Transcript analysis by cBROCA
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
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: SCV001551631.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The CHEK2 c.320-5T>A variant was identified in 40 of 33888 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian, pancreatic, and colon cancer, … (more)
The CHEK2 c.320-5T>A variant was identified in 40 of 33888 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian, pancreatic, and colon cancer, as well as non-Hodkin lymphoma and the variant was present in 1 of 10976 control chromosomes (frequency: 0.00009) from healthy individuals (Decker 2017, Havranek 2015, Mucaki 2016, Yurgelun 2015, Kraus 2017, Kleibl 2008, Kleibl 2009, Mohelnikova-Duchonova 2010). The variant was also identified in dbSNP (ID: rs121980700) as “With uncertain significance”. The variant was also identified in ClinVar (as benign by Invitae, likely benign by University of Washington, LabCorp, and Ambry and uncertain significance by Quest, ARUP and Gene Dx). The variant was not identified in Cosmic, MutDB or Zhejiang University databases. The variant was identified in control databases in 151 of 276520 chromosomes (1 homozygous) at a frequency of 0.0005 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 6 of 6458 chromosomes (freq: 0.009), Latino in 33 of 34412 chromosomes (freq: 0.001), European Non-Finnish in 71 of 126074 chromosomes (freq: 0.0006), Ashkenazi Jewish in 40 of 10146 chromosomes (freq: 0.004), and South Asian in 1 of 30776 chromosomes (freq: 0.00003). The variant was not observed in the African, East Asian, or Finnish populations. The c.320-5T>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. Reverse transcription PCR analysis on blood from an individual with breast or ovarian cancer demonstrated that this variant leads to an in frame transcript lacking exon 3 and 4; however the shortened transcript was present at levels less than 20% that of the wild-type transcript suggesting that this variant does not abolish normal splicing (Kraus, 2017). However, 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In addition the variant was identified as co-occurring with a pathogenic BRCA2 variant (c.5857G>T, p.Glu1953X) by our laboratory in an affected individual, indicating that the variant c.320-5T>A may not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
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Benign
(Sep 27, 2021)
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no assertion criteria provided
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: SCV001977053.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
germline
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Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague
Accession: SCV000154113.1
First in ClinVar: Jun 04, 2014 Last updated: Jun 04, 2014
Comment:
Characterized in 1 out of 673 breast cancer patients, 1 out of 631 colorectal cancer patients, 1 out of 259 pancreatic cancer patients, 1 out … (more)
Characterized in 1 out of 673 breast cancer patients, 1 out of 631 colorectal cancer patients, 1 out of 259 pancreatic cancer patients, 1 out of 340 Non Hodgkin lymphoma patients and in none of 683 non cancer controls (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 |
---|---|---|---|---|
Comprehensive analysis and ACMG-based classification of CHEK2 variants in hereditary cancer patients. | Vargas-Parra G | Human mutation | 2020 | PMID: 32906215 |
Characterization of splice-altering mutations in inherited predisposition to cancer. | Casadei S | Proceedings of the National Academy of Sciences of the United States of America | 2019 | PMID: 31843900 |
Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. | Tsai GJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30374176 |
Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings. | Bonache S | Journal of cancer research and clinical oncology | 2018 | PMID: 30306255 |
Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer. | Hampel H | JAMA oncology | 2018 | PMID: 29596542 |
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 |
Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. | Kraus C | International journal of cancer | 2017 | PMID: 27616075 |
Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing. | Balmaña J | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 27621404 |
A unified analytic framework for prioritization of non-coding variants of uncertain significance in heritable breast and ovarian cancer. | Mucaki EJ | BMC medical genomics | 2016 | PMID: 27067391 |
Multigene testing of moderate-risk genes: be mindful of the missense. | Young EL | Journal of medical genetics | 2016 | PMID: 26787654 |
Association of Germline CHEK2 Gene Variants with Risk and Prognosis of Non-Hodgkin Lymphoma. | Havranek O | PloS one | 2015 | PMID: 26506619 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. | Castéra L | European journal of human genetics : EJHG | 2014 | PMID: 24549055 |
Alterations of CHEK2 forkhead-associated domain increase the risk of Hodgkin lymphoma. | Havranek O | Neoplasma | 2011 | PMID: 21744992 |
CHEK2 gene alterations in the forkhead-associated domain, 1100delC and del5395 do not modify the risk of sporadic pancreatic cancer. | Mohelnikova-Duchonova B | Cancer epidemiology | 2010 | PMID: 20643596 |
The CHEK2 gene I157T mutation and other alterations in its proximity increase the risk of sporadic colorectal cancer in the Czech population. | Kleibl Z | European journal of cancer (Oxford, England : 1990) | 2009 | PMID: 18996005 |
Analysis of CHEK2 FHA domain in Czech patients with sporadic breast cancer revealed distinct rare genetic alterations. | Kleibl Z | Breast cancer research and treatment | 2008 | PMID: 18058223 |
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Text-mined citations for rs121908700 ...
HelpRecord last updated May 08, 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.