NM_007194.4(CHEK2):c.444+1G>A AND CHEK2-related cancer predisposition

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Sep 21, 2018
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV004556730.3

Allele description [Variation Report for NM_007194.4(CHEK2):c.444+1G>A]

NM_007194.4(CHEK2):c.444+1G>A

Gene:

CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q12.1

Genomic location:

Preferred name:

NM_007194.4(CHEK2):c.444+1G>A

Other names:

IVS3+1G>A

HGVS:

NC_000022.11:g.28725242C>T
NG_008150.2:g.21625G>A
NM_001005735.2:c.573+1G>A
NM_001257387.2:c.-334+1G>A
NM_001349956.2:c.444+1G>A
NM_007194.4:c.444+1G>AMANE SELECT
NM_145862.2:c.444+1G>A
LRG_302t1:c.444+1G>A
LRG_302:g.21625G>A
NC_000022.10:g.29121230C>T
NM_001005735.1:c.573+1G>A
NM_007194.3:c.444+1G>A

Note:

NCBI staff provided an HGVS expression for allelic variant 604373.0013 by confirming that the allele introduced an Hpy188 III site in the product of primers Ch2/3f and Ch2/3r Cybulski et al.,2004 (PubMed 15492928).

Nucleotide change:

IVS2DS, G-A, +1

Links:

OMIM: 604373.0013; dbSNP: rs121908698

NCBI 1000 Genomes Browser:

rs121908698

Molecular consequence:

NM_001005735.2:c.573+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001257387.2:c.-334+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001349956.2:c.444+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_007194.4:c.444+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_145862.2:c.444+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Functional consequence:

sequence variant affecting splice donor [Sequence Ontology: SO:1000072]

Condition(s)

Name:: CHEK2-related cancer predisposition
Synonyms:: CHEK2-Related Cancer Susceptibility
Identifiers:: MONDO: MONDO:0700271; MedGen: CN377760

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000915969	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Sep 21, 2018)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 25583358, 15087378, 21876083, 26446916, 15492928, 24713400, 12533788 Citation Link,
SCV001749588	GenomeConnect - Invitae Patient Insights Network	no classification provided	not provided	unknown	phenotyping only
SCV004046200	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000915969

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Likely pathogenic
(Sep 21, 2018)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV001749588

GenomeConnect - Invitae Patient Insights Network

no classification provided

not provided

unknown

phenotyping only

SCV004046200

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	phenotyping only

Citations

PubMed

CHEK2 mutations and the risk of papillary thyroid cancer.

Siołek M, Cybulski C, Gąsior-Perczak D, Kowalik A, Kozak-Klonowska B, Kowalska A, Chłopek M, Kluźniak W, Wokołorczyk D, Pałyga I, Walczyk A, Lizis-Kolus K, Sun P, Lubiński J, Narod SA, Góźdż S.

Int J Cancer. 2015 Aug 1;137(3):548-52. doi: 10.1002/ijc.29426. Epub 2015 Jan 28.

PubMed [citation]

PMID:: 25583358

A novel founder CHEK2 mutation is associated with increased prostate cancer risk.

Cybulski C, Huzarski T, Górski B, Masojć B, Mierzejewski M, Debniak T, Gliniewicz B, Matyjasik J, Złowocka E, Kurzawski G, Sikorski A, Posmyk M, Szwiec M, Czajka R, Narod SA, Lubiński J.

Cancer Res. 2004 Apr 15;64(8):2677-9.

PubMed [citation]

PMID:: 15087378

See all PubMed Citations (8)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000915969.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The CHEK2 c.444+1G>A variant, also reported as IVS2+1G>A, occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant is well described in the literature in over 100 probands, and is associated particularly with familial prostate cancer and breast cancer (Dong et al. 2003, Cybulski et al. 2004a, Cybulski et al. 2004b, Cybulski et al. 2011, BÄ…k et al. 2014, Borun et al. 2015, SioÅ‚ek et al. 2015) with odds ratios for familial prostate cancer of up to 12.1 (Cybulski et al. 2004b) and breast cancer of 3.0 (BÄ…k et al. 2014). The c.444+1G>A variant is reported at a frequency of 0.000465 in the European (non-Finnish) population of the Genome Aggregation Database. The c.444+1G>A variant has been shown to be one of three CHEK2 founder variants in the Polish population. Functional studies by Dong et al. (2003) demonstrated that the c.444+1G>A variant creates a premature stop codon, which removes part of the FHA domain of the protein and the entire kinase activation domain, and western blot analysis showed dramatic reduction of CHEK2 protein levels in cell lines from the proband. Based on the evidence, the c.444+1G>A variant is classified as likely pathogenic for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GenomeConnect - Invitae Patient Insights Network, SCV001749588.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Pathogenic and reported on 06-11-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046200.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant is also referred to as IVS2+1G>A in the literature. The c.573+1G>A variant affects the canonical splice donor site of intron 4 and is therefore predicted to interfere with splicing and result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with familial prostate cancer and breast cancer with odds ratios for familial prostate cancer of up to 12.1 and breast cancer of 3.0 (PMID: 12533788, 15492928, 21876083, 24713400, 25583358). This variant has also been associated with increased risk of other cancers including colon, thyroid and ovarian cancer and polycythemia vera (PMID: 15492928, 26084796, 26681312, 30322717). RNA analysis of cell lines derived from patient cells demonstrated that this variant results in reduced protein levels and use of another splice donor site, leading to frameshift and creation of a premature termination codon (PMID: 12533788). It is present in the heterozygous state in the gnomAD population database at a frequency of .014% (40/282678) and thus is presumed to be rare. Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. Based on the available evidence, the c.573+1G>A variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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