ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.793-1G>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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007194.4(CHEK2):c.793-1G>A
Variation ID: 182430 Accession: VCV000182430.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28710060 (GRCh38) [ NCBI UCSC ] 22: 29106048 (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 Dec 19, 2017 May 1, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.793-1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001005735.2:c.922-1G>A splice acceptor NM_001257387.2:c.130-1G>A splice acceptor NM_001349956.2:c.592-1G>A splice acceptor NM_145862.2:c.793-1G>A splice acceptor NC_000022.11:g.28710060C>T NC_000022.10:g.29106048C>T NG_008150.2:g.36807G>A LRG_302:g.36807G>A LRG_302t1:c.793-1G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000022.11:28710059:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- cryptic splice acceptor activation Variation Ontology [VariO:0375]
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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 |
3989 | 4043 |
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
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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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2023 | RCV000160429.12 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 13, 2023 | RCV000214915.17 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 28, 2024 | RCV000464029.15 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 27, 2021 | RCV002498796.3 |
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
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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
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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Pathogenic
(Jun 02, 2017)
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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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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839943.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
This c.793-1G>A variant in the CHEK2 gene has not been observed in our cohort database nor has been detected in the ExAC database. This variant … (more)
This c.793-1G>A variant in the CHEK2 gene has not been observed in our cohort database nor has been detected in the ExAC database. This variant was however reported in ClinVar but the clinical presentation of the patients was not available (SCV000210975.9, SCV000273338.2). This variant affect the invariant acceptor splice site of intron 6 of the CHEK2 gene. While not clinically validated, computer-based algorithms predict this c.793-1G>A change to affect splicing by creating an alternative splice site 1bp downstream and thus creating a frameshift. This variant is classified as pathogenic. (less)
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Pathogenic
(Mar 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
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GeneKor MSA
Accession: SCV000890134.1
First in ClinVar: Nov 30, 2019 Last updated: Nov 30, 2019 |
Comment:
This sequence change occurs 1 base before exon 7 of the CHEK2 gene. This position is highly conserved in the human and other genomes and … (more)
This sequence change occurs 1 base before exon 7 of the CHEK2 gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083; PMID: 24713400). This mutation has been reported in individuals who underwent genetic testing for the risk of hereditary cancer, including breast cancer (PMID: 27751358). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this change disrupts the wild type acceptor site and activates an intronic cryptic splice acceptor 1 bp downstream, thus creating a frameshift. Experimental analysis in patient-derived leukocytes using RT-PCR of mRNA followed by cDNA sequencing showed that this variant affects splicing by creating an alternative splice site 1 bp downstream which results in a frameshift effect and the generation of a premature translation stop signal 10 amino acid residues later, and is predicted to result in a truncated protein. For these reasons, this variant has been classified as Pathogenic. (less)
Sex: female
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Likely pathogenic
(Jul 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Colorectal cancer Familial prostate carcinoma Bone osteosarcoma Li-Fraumeni syndrome 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809367.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 15, 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: SCV004217509.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Feb 14, 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: SCV004221756.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This variant disrupts a canonical splice-acceptor site and interferes with normal CHEK2 mRNA splicing. The frequency of this variant in the general population, 0.00012 (4/34412 … (more)
This variant disrupts a canonical splice-acceptor site and interferes with normal CHEK2 mRNA splicing. The frequency of this variant in the general population, 0.00012 (4/34412 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 26681312 (2015)), prostate cancer (PMID: 29520813 (2018)), and neuroblastoma (PMID: 27009842 (2016)), as well as an individual who underwent genetic testing for hereditary cancer risk (PMID: 31349801 (2019)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jan 28, 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: SCV000550453.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 6 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects an acceptor splice site in intron 6 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs730881687, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with breast cancer and prostate cancer (PMID: 26681312, 27751358, 29520813, 31349801; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182430). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 31349801; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 13, 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: SCV000537628.6
First in ClinVar: May 29, 2016 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G>A nucleotide substitution at the -1 position of intron 6 of the CHEK2 gene. Splice site prediction tools suggest that this … (more)
This variant causes a G>A nucleotide substitution at the -1 position of intron 6 of the CHEK2 gene. Splice site prediction tools suggest that this variant may abolish the canonical splice acceptor site and create a new splice acceptor one basepair downstream. RNA studies have confirmed this prediction, with the variant resulting in the deletion of one nucleotide from the mRNA and a frameshift and premature termination codon within exon 7 of the protein (p.Asp265Thrfs*10) (PMID: 31349801, 37725924). This variant has been reported in individuals affected with breast cancer (PMID: 26556299, 26681312, 27751358, 31349801, 36529819) and prostate cancer (PMID: 29520813) in the literature. This variant has been reported in a homozygous individual with a personal and family history of cancer and multiple cytogenetic anomalies (PMID: 36529819). This variant has been identified in 4/249694 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely pathogenic
(Jan 17, 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: SCV000785943.2
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
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Likely pathogenic
(Feb 01, 2023)
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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: SCV000210975.17
First in ClinVar: Feb 24, 2015 Last updated: Nov 11, 2023 |
Comment:
Canonical splice site variant demonstrated to result in aberrant splicing, leading to protein truncation or nonsense mediated decay in a gene for which loss-of-function is … (more)
Canonical splice site variant demonstrated to result in aberrant splicing, leading to protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Agiannitopoulos et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast, prostate, and other cancers (Leedom et al., 2016; Schrader et al., 2016; Lilyquist et al., 2017; Wu et al., 2018, Agiannitopoulos et al., 2019; Germani et al., 2020); This variant is associated with the following publications: (PMID: 31589614, 32805687, 27751358, 26681312, 26556299, 24713400, 21876083, 25980754, 29520813, 31447099, 22419737, 19782031, 36425062, 35261632, 27009842, 31349801, 31970404, 28888541, 32957588) (less)
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Likely pathogenic
(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: SCV004020113.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either … (more)
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. (less)
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Pathogenic
(Mar 27, 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: SCV000273338.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The c.793-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 6 of the CHEK2 gene. One study identified … (more)
The c.793-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 6 of the CHEK2 gene. One study identified this alteration in 1/703 patients with lethal prostate cancer and 0/1455 patients with localized prostate cancer (Wu Y et al. Prostate, 2018 Jun;78:607-615). This alteration has also been detected in multiple individuals undergoing multi-gene panel testing (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32; Leedom TP et al. Cancer Genet. 2016 Sep;209:403-407). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Agiannitopoulos K et al. BMC Med. Genet., 2019 07;20:131). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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cryptic splice acceptor activation
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GeneKor MSA
Accession: SCV000890134.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52 CHEK2 Splice-Site Variants. | Sanoguera-Miralles L | Clinical chemistry | 2024 | PMID: 37725924 |
Two unrelated cases with biallelic CHEK2 variants:a novel condition with constitutional chromosomal instability? | Bottillo I | European journal of human genetics : EJHG | 2023 | PMID: 36529819 |
Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers. | Germani A | Journal of clinical medicine | 2020 | PMID: 32957588 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
Characterization of the c.793-1G > A splicing variant in CHEK2 gene as pathogenic: a case report. | Agiannitopoulos K | BMC medical genetics | 2019 | PMID: 31349801 |
A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. | Wu Y | The Prostate | 2018 | PMID: 29520813 |
Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers. | Leedom TP | Cancer genetics | 2016 | PMID: 27751358 |
Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression. | Lasorsa VA | Oncotarget | 2016 | PMID: 27009842 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. | Schrader KA | JAMA oncology | 2016 | PMID: 26556299 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
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Text-mined citations for rs730881687 ...
HelpRecord last updated Jun 23, 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.