VCV000128075.110 - ClinVar

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

Germline

Classification

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.

(54)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 128075 Accession: VCV000128075.110

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q12.1 22: 28725242 (GRCh38) [ NCBI UCSC ] 22: 29121230 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Mar 20, 2016	Nov 3, 2024	Oct 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_007194.4:c.444+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001005735.2:c.573+1G>A		splice donor
NM_001257387.2:c.-334+1G>A		splice donor
NM_001349956.2:c.444+1G>A		splice donor
NM_145862.2:c.444+1G>A		splice donor
NC_000022.11:g.28725242C>T
NC_000022.10:g.29121230C>T
NG_008150.2:g.21625G>A
LRG_302:g.21625G>A
LRG_302t1:c.444+1G>A

... more HGVS ... less HGVS

Protein change

Other names

IVS3+1G>A
IVS2DS, G-A, +1

Canonical SPDI

NC_000022.11:28725241:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00008

The Genome Aggregation Database (gnomAD) 0.00009

Links

ClinGen: CA288309 OMIM: 604373.0013 dbSNP: rs121908698 VarSome

Comment on variant

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).

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
Gene	OMIM	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.
CHEK2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4053	4109

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.
Hereditary cancer-predisposing syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 5, 2023	RCV000116017.27
Familial cancer of breast	Pathogenic/Likely pathogenic (16)	criteria provided, multiple submitters, no conflicts	Mar 27, 2024	RCV000196718.40
Breast and colorectal cancer, susceptibility to	Pathogenic (1)	criteria provided, single submitter	Nov 20, 2015	RCV000210090.8
not provided	Pathogenic (16)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000212418.55
Breast cancer, susceptibility to	Pathogenic (1)	criteria provided, single submitter	Sep 29, 2016	RCV000501923.10
Bone osteosarcoma Familial cancer of breast Li-Fraumeni syndrome 2 Malignant tumor of prostate	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763475.7
Familial cancer of breast Li-Fraumeni syndrome 2	Pathogenic (1)	no assertion criteria provided	Sep 1, 2019	RCV001171461.8
Malignant tumor of breast	Pathogenic (1)	no assertion criteria provided	-	RCV001354639.7
Breast carcinoma	Pathogenic (1)	no assertion criteria provided	Aug 9, 2021	RCV001554253.6
Breast and/or ovarian cancer	Pathogenic (2)	criteria provided, single submitter	Jun 16, 2023	RCV001270936.7
Li-Fraumeni syndrome 2	Pathogenic (1)	criteria provided, single submitter	Jul 12, 2024	RCV001705823.7
Colorectal cancer	Pathogenic (1)	criteria provided, single submitter	Aug 17, 2022	RCV002463642.5
Melanoma	Pathogenic (1)	criteria provided, single submitter	Dec 5, 2022	RCV002508922.5
Endometrial carcinoma	Pathogenic (1)	no assertion criteria provided	Feb 21, 2023	RCV003128145.5
TUMOR PREDISPOSITION SYNDROME 4, BREAST/PROSTATE	Pathogenic (1)	no assertion criteria provided	Nov 1, 2006	RCV003333693.1
CHEK2-related cancer predisposition	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 21, 2018	RCV004556730.3
Inherited breast cancer and ovarian cancer	Likely pathogenic (1)	criteria provided, single submitter	Oct 29, 2024	RCV004772840.1
CHEK2-related disorder	Pathogenic (1)	no assertion criteria provided	Aug 27, 2024	RCV004737199.1
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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.
Pathogenic (May 25, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000839944.1 First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018	Comment: This c.444+1G>A variant in the CHEK2 gene has been reported in patients with breast cancer [PMID 21876083, 27616075, 26822949, 24713400 referred as IVS2+1G>A]. This variant … (more) This c.444+1G>A variant in the CHEK2 gene has been reported in patients with breast cancer [PMID 21876083, 27616075, 26822949, 24713400 referred as IVS2+1G>A]. This variant was also reported in a cohort of patients with thyroid cancer [PMID 25583358], prostate cancer [PMID 12533788] and multiple types of cancer [PMID 15492928]. This variant was also detected in one patient with breast cancer who was compound heterozygous for this c.444+1G>A variant and the p.I157T pathogenic variant [PMID 2471340]. This variant affects the invariant donor splice site of intron 3 of the CHEK2 gene. While not validated for clinical use, computer-based algorithms predict this c.444+1G>A change to disrupt this splicing site. This variant was detected in 14 heterozygous individuals within the ExAC database (http://exac.broadinstitute.org/variant/22-29121230-C-T). This variant is classified as pathogenic. (less)
Likely pathogenic (Sep 21, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	CHEK2-Related Cancer Susceptibility Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915969.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (7) PubMed: 25583358‚ 15087378‚ 21876083‚ 26446916‚ 15492928‚ 24713400‚ 12533788 Comment: 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 … (more) 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. (less)
Pathogenic (Nov 22, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917232.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (5) PubMed: 12533788‚ 27616075‚ 26822949‚ 27153395‚ 21876083 Comment: Variant summary: The CHEK2 c.444+1G>A variant involves the alteration of a conserved intronic nucleotide that is the first nucleotide of the intron at an exon-intron … (more) Variant summary: The CHEK2 c.444+1G>A variant involves the alteration of a conserved intronic nucleotide that is the first nucleotide of the intron at an exon-intron junction. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a loss of the canonical splice site, which is supported by functional studies that show the use of a cryptic splice site in patient cell lines that introduces 4bp, thus causing a frameshift. A concomitant reduction in CHEK2 protein was also detected in these patient cell lines, supporting the splicing data (Dong_2003). The variant has been identified in numerous patients with breast and prostate cancer (Kraus_2016, Maxwell_2016, Lhota_2016). The variant reportedly identified among BrC patients at a frequency of 1.3% and is considered to be one of the four founder mutations in Poland (Cybulski_2011). This variant was found in 39/278078 control chromosomes at a frequency of 0.0001402, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446511.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Sex: female
Pathogenic (Jul 19, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000186195.9 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (12) PubMed: 12533788‚ 15492928‚ 19030985‚ 21876083‚ 23296741‚ 27616075‚ 27751358‚ 28211887‚ 28727877‚ 28802053‚ 29902706‚ 29958926 Comment: The c.444+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the CHEK2 gene. This mutation has … (more) The c.444+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the CHEK2 gene. This mutation has been described in numerous breast cancer patients, including individuals with bilateral breast cancer (Kraus C et al. Int. J. Cancer 2017 Jan;140(1):95-102; Pelttari LM et al. Clin. Genet. 2018 Mar;93(3):595-602). In addition, this mutation has been associated with increased risk of breast, prostate, thyroid, and stomach cancers as well as polycythaemia vera in Polish patient cohorts (Cybulski C et al. Am. J. Hum. Genet. 2004 Dec;75:1131-5; Serrano-Fernandez P et al. Breast Cancer Res. Treat. 2009 Sep;117:161-5; Cybulski C et al. J. Clin. Oncol. 2011 Oct;29:3747-52; Teodorczyk U et al. Fam. Cancer. 2013 Sep;12:473-8; Janiszewska H et al. Br. J. Haematol. 2016 Apr;173(1):150-2). Of note, this alteration is also designated as IVS2+1G>A in published literature. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. As such, this alteration is classified as a disease-causing mutation. (less)
Pathogenic (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004217503.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Nov 20, 2015)	criteria provided, single submitter (Shirts et al. (Genet Med 2016)) Method: clinical testing	Breast and colorectal cancer, susceptibility to Affected status: yes Allele origin: germline	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV000266069.1 First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016	Number of individuals with the variant: 1 Clinical Features: breast cancer (present) Age: 60-69 years
Pathogenic (Sep 29, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	{Breast cancer, susceptibility to} Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000594120.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001141371.1 First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020
Pathogenic (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	GeneKor MSA Accession: SCV000821730.2 First in ClinVar: Oct 10, 2018 Last updated: Apr 22, 2020	Comment: This variation occurs one base after exon 3 of the CHEK2 gene in a position highly conserved in the human and other genomes that is … (more) This variation occurs one base after exon 3 of the CHEK2 gene in a position highly conserved in the human and other genomes that is crucial for mRNA processing. This is expected to result in incorrect splicing and likely results in an absent or disrupted protein product. This variant has been reported in literature in individuals with increased risk for breast, prostate and other cancers (PMID:15492928, PMID: 19030985, PMID:12533788, PMID: 15492928). This variant is also known as IVS2+1G>A in the literature. The mutation database ClinVar contains entries for this variant (Variation ID: 128075). Algorithms developed to predict the effect of single base changes on mRNA splicing suggest that this variant may alter this cellular process. Moreover, experimental studies support the pathogenic effect of this variant through in mRNA splicing (PMID: 12533788). (less)
Pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440944.1 First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020
Pathogenic (Apr 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499789.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (Dec 15, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial cancer of breast Affected status: no Allele origin: germline	Department of Pediatrics, Memorial Sloan Kettering Cancer Center Accession: SCV001478115.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Publications: PubMed (1) PubMed: 28873162
Pathogenic (Nov 30, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002537436.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The CHEK2 c.444+1G>A variant, also known as IVS2+1G>A in the literature, is a well-known pathogenic variant associated with breast and other cancers (PMID: 12533788, 31843900, … (more) The CHEK2 c.444+1G>A variant, also known as IVS2+1G>A in the literature, is a well-known pathogenic variant associated with breast and other cancers (PMID: 12533788, 31843900, 19030985, 21876083, 15492928, 24713400). The c.444+1G>A variant has been shown to be one of three CHEK2 founder variants in the Polish population (PMID: 15492928). In case-control studies the variant was shown to be associated with breast cancer (OR: 2.3-3.0, p=0.04), melanoma (OR: 3.3, p=0.3), prostate cancer (OR: 2.5, p=0.05), stomach cancer (OR: 3.5, p=0.05), and thyroid cancer (OR: 6.2, p=0.0003) (PMID: 15492928, 24713400). Functional studies have shown that this variant alters splicing and results in decreased CHEK2 expression (PMID: 12533788, 31843900). This variant has been reported in ClinVar (Variation ID: 128075). This variant was observed in 13/25122 chromosomes in the Finnish population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (6) PubMed: 12533788‚ 31843900‚ 19030985‚ 21876083‚ 15492928‚ 24713400
Pathogenic (Aug 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579688.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS3, PS4_MOD	Number of individuals with the variant: 6 Sex: female
Pathogenic (Sep 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin Additional submitter: CUBI - Core Unit Bioinformatics, Berlin Institute of Health Accession: SCV002578144.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022	Sex: female Tissue: Blood
Pathogenic (Mar 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Laboratory Cellgenetics, GMDL Cellgenetics Accession: SCV002578254.1 First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022	Publications: PubMed (4) PubMed: 27616075‚ 27153395‚ 26822949‚ 15492928 Comment: The variant CHEK2:c.444+1G>A was classified as Pathogenic. The classification was assigned based on the following ACMG criteria: PVS1, PS3, PS4_moderate, PM2, PP5. Clinical Features: Breast carcinoma (present)
Pathogenic (Aug 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV002758572.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Comment: ACMG criteria used to clasify this variant: PVS1, PM2, PS4
Pathogenic (Apr 17, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556670.2 First in ClinVar: Aug 04, 2022 Last updated: Dec 17, 2022
Pathogenic (Dec 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Melanoma Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV002818309.1 First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023	Comment: ACMG criteria used to clasify this variant: PVS1, PM2, PS4
Pathogenic (Dec 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial cancer of breast Affected status: no Allele origin: germline	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001366166.4 First in ClinVar: Jul 04, 2020 Last updated: Feb 25, 2023	Comment: PVS1, PS3, PS4_STR, BS1
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002009496.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004024661.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CHEK2-related cancer predisposition Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046200.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (May 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004225016.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (13) PubMed: 12533788‚ 15492928‚ 15810020‚ 20417869‚ 24713400‚ 27616075‚ 29520813‚ 30927251‚ 31843900‚ 32875559‚ 33804961‚ 34308366‚ 34992046 Comment: PS4_moderate, PVS1 Number of individuals with the variant: 35
Pathogenic (Apr 24, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019277.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jun 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV004240453.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Dec 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000537642.5 First in ClinVar: Mar 24, 2017 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 12533788‚ 15087378‚ 15095295‚ 15492928‚ 21876083‚ 24713400‚ 31843900‚ 32546565‚ 33030641 Comment: This variant causes a G to A nucleotide substitution at the +1 position of intron 3 of the CHEK2 gene. It is also known as … (more) This variant causes a G to A nucleotide substitution at the +1 position of intron 3 of the CHEK2 gene. It is also known as CHEK2 IVS2+1G>A in the literature. RNA studies have shown that this variant abolishes the native splice donor site and activates a cryptic splice site, which leads to a frameshift and premature protein truncation (PMID: 12533788, 31843900). This variant has been reported in numerous individuals affected breast cancer (PMID: 15095295, 15492928, 21876083, 24713400, 33030641), ovarian cancer (PMID: 32546565), and prostate cancer (PMID: 12533788, 15087378). A large case-control study has shown that this variant is associated with an increased risk of breast cancer (OR=2.085, 95%CI [1.34 to 3.245], PMID: 33471991). The variant is thought to be a founder mutation in the Polish population (PMID: 15087378, 15492928). This variant has been identified in 40/282678 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 Pathogenic. (less)
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000253902.13 First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 28492532‚ 15492928‚ 19030985‚ 24713400‚ 12533788 Comment: This sequence change affects a donor splice site in intron 3 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces … (more) This sequence change affects a donor splice site in intron 3 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 (rs121908698, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with an increased risk (OR=2.3-3.5) for familial breast cancer or an increased risk (OR=2.5) for prostate cancer (PMID: 15492928, 19030985, 24713400; 21876083 12533788). This variant is also known as IVS2+1G>A. ClinVar contains an entry for this variant (Variation ID: 128075). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 12533788; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 12, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001934406.2 First in ClinVar: Sep 25, 2021 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PS4,PS1_SUP Clinical Features: Family history of cancer (present) , Cardiac arrhythmia (present) Sex: female
Likely pathogenic (Oct 29, 2024)	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020) Method: clinical testing	Inherited breast cancer and ovarian cancer Affected status: yes Allele origin: germline	Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service Accession: SCV005382632.1 First in ClinVar: Nov 03, 2024 Last updated: Nov 03, 2024	Comment: PVS1,PM5_Supporting
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Familial prostate cancer Bone osteosarcoma Li-Fraumeni syndrome 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894257.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Likely pathogenic (Jan 24, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000488172.2 First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022	Publications: PubMed (8) PubMed: 15810020‚ 15095295‚ 21876083‚ 15492928‚ 12533788‚ 24713400‚ 25583358‚ 17085682
Pathogenic (Jun 24, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149926.15 First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023	Comment: Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population … (more) Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25980754, 25583358, 15095295, 27751358, 28918466, 30322717, 30927251, 31159747, 33077847, 32885271, 32338768, 33726816, 21876083, 25525159, 25915596, 26083025, 26250988, 25619955, 26084796, 15492928, 22058216, 19030985, 23296741, 26822949, 27153395, 26629066, 26929905, 26296701, 27038244, 24713400, 12533788, 16914568, 27616075, 27783279, 28727877, 28802053, 15810020, 27488870, 28680382, 28211887, 29356917, 29067458, 17085682, 29520813, 29902706, 29958926, 26681312, 30426508, 31447099, 34308366, 34570182) (less)
Pathogenic (Mar 09, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004020198.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Publications: PubMed (1) PubMed: 25085752 Comment: This variant is considered pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants … (more) This variant is considered pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. (less)
Pathogenic (Apr 02, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000601168.5 First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024	Publications: PubMed (36) PubMed: 28779002‚ 12533788‚ 21876083‚ 15095295‚ 15810020‚ 19030985‚ 22058216‚ 25525159‚ 25980754‚ 26084796‚ 26681312‚ 26689913‚ 26822949‚ 27153395‚ 27616075‚ 28727877‚ 28802053‚ 29520813‚ 29902706‚ 30322717‚ 30426508‚ 30676620‚ 30927251‚ 31159747‚ 31263571‚ 31360903‚ 31447099‚ 32338768‚ 32885271‚ 33077847‚ 33726816‚ 34308366‚ 34570182‚ 24713400‚ 25583358‚ 15492928 Comment: This variant disrupts a canonical splice-donor site and interferes with normal CHEK2 mRNA splicing. In the published literature, the variant has been reported in individuals … (more) This variant disrupts a canonical splice-donor site and interferes with normal CHEK2 mRNA splicing. In the published literature, the variant has been reported in individuals and families with hereditary cancer (PMIDs: 28779002 (2017), 25583358 (2015), 24713400 (2014), 21876083 (2011), and 15492928 (2004)). The frequency of this variant in the general population, 0.00052 (13/25122 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Nov 22, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004564994.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Comment: The CHEK2 c.444+1G>A variant (rs121908698), also known as IVS2+1G>A, is reported in numerous individuals with familial breast cancer and prostate cancer, and is considered to … (more) The CHEK2 c.444+1G>A variant (rs121908698), also known as IVS2+1G>A, is reported in numerous individuals with familial breast cancer and prostate cancer, and is considered to be one of three CHEK2 founder variants in the Polish population (Bak 2014, Cybulski 2004, Cybulski 2006, Dong 2003). Functional analysis showed that this variant results in a 4-bp insertion due to abnormal splicing and creates a premature termination codon eliminating part of the FHA domain and the entire kinase activation domain of CHEK2 (Dong 2003). This variant is reported in ClinVar (Variation ID: 128075). It is observed in the general population with an overall allele frequency of 0.01% (40/282678 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: Bak A et al. A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland. Hered Cancer Clin Pract. 2014 Apr 8;12(1):10. PMID: 24713400. Cybulski C et al. A novel founder CHEK2 mutation is associated with increased prostate cancer risk. Cancer Res. 2004 Apr 15;64(8):2677-9. PMID: 15087378. Cybulski C et al. CHEK2-positive breast cancers in young Polish women. Clin Cancer Res. 2006 Aug 15;12(16):4832-5. PMID: 16914568. Dong X et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003 Feb;72(2):270-80. PMID: 12533788. (less)
Pathogenic (Oct 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197505.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001245716.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Comment: CHEK2: PVS1, PS4, PM2:Supporting Number of individuals with the variant: 12
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002035817.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Pathogenic (Nov 01, 2006)	no assertion criteria provided Method: literature only	TUMOR PREDISPOSITION SYNDROME 4, BREAST/PROSTATE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026133.2 First in ClinVar: Apr 04, 2013 Last updated: Nov 24, 2017	Publications: PubMed (2) PubMed: 15492928‚ 17085682 Comment on evidence: Cybulski et al. (2004) identified a G-to-A transition in a splice site of exon 2 of the CHEK2 gene (IVS2+1G-A), which results in a 4-bp … (more) Cybulski et al. (2004) identified a G-to-A transition in a splice site of exon 2 of the CHEK2 gene (IVS2+1G-A), which results in a 4-bp insertion as a result of abnormal splicing and creates a termination codon in exon 3, in patients with several different types of cancer, including breast and prostate (see TPDS4, 609265) Cybulski et al. (2006) identified the IVS2+1G-A mutation in 15 (0.8%) of 1,864 Polish men with prostate cancer, 5 (2.0%) of 249 patients with familial prostate cancer, and 22 (0.4%) of 5496 controls. Data analysis yielded an odds ratio of 5.1 for familial prostate cancer in carriers of the splice site mutation. The authors determined that it is a founder mutation. (less)
Pathogenic (Sep 01, 2019)	no assertion criteria provided Method: research	Familial cancer of breast Li-Fraumeni syndrome 2 Affected status: yes Allele origin: germline	King Laboratory, University of Washington Accession: SCV001251372.1 First in ClinVar: Jun 07, 2020 Last updated: Jun 07, 2020 Comment: Transcript analysis by cBROCA	Publications: PubMed (1) PubMed: 31843900
Pathogenic (Jun 11, 2019)	no assertion criteria provided Method: clinical testing	Breast and/or ovarian cancer Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV001451740.1 First in ClinVar: Dec 24, 2020 Last updated: Dec 24, 2020	Publications: PubMed (1) PubMed: 32295079 Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Malignant tumor of breast Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001549303.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The CHEK2 c.444+1G>A variant was identified in 179 of 121122 proband chromosomes (frequency: 0.002) from individuals or families with ascertained in studies of various cancers … (more) The CHEK2 c.444+1G>A variant was identified in 179 of 121122 proband chromosomes (frequency: 0.002) from individuals or families with ascertained in studies of various cancers and was present in 23 of 11230 control chromosomes (frequency: 0.002) from healthy individuals (Bak 2014, Cybulski 2004, Cybulski 2011, Dong 2003, Havranek 2015, Janiszewska 2016, Leedom 2016, Sioek 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs121908698) as With Pathogenic allele, and ClinVar (classified as pathogenic by GeneDx, Ambry Genetics, Invitae, Color Genomics and two clinical laboratories; classified as likely benign by Counsyl). The variant was not identified in Zhejiang Colon Cancer Database. The variant was identified in control databases in 39 of 277022 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: Other in 3 of 6464 chromosomes (freq: 0.001), European Non-Finnish in 24 of 126516 chromosomes (freq: 0.0002), European Finnish in 12 of 25792 chromosomes (freq: 0.001), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The c.444+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. The c.444+1G>A variant was shown to results in a 4-bp insertion due to an abnormal splicing, using an alternative splice donor site in intron 2. This variant eliminates part of forkhead-homology associated domain and the entire kinase activation domain of CHEK2 (Dong 2003, Havranek 2015). In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less)
Pathogenic (Aug 09, 2021)	no assertion criteria provided Method: clinical testing	Breast carcinoma Affected status: yes Allele origin: germline	Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences Accession: SCV001774858.1 First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021	Age: 30-39 years
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001906267.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954716.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001809764.2 First in ClinVar: Aug 25, 2021 Last updated: Oct 16, 2021
Pathogenic (Aug 26, 2022)	no assertion criteria provided Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV002588967.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Pathogenic (Feb 21, 2023)	no assertion criteria provided Method: clinical testing	Endometrial carcinoma Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV003804360.1 First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023	Number of individuals with the variant: 2 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
Pathogenic (Aug 27, 2024)	no assertion criteria provided Method: clinical testing	CHEK2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005350749.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The CHEK2 c.444+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant (previously known as IVS2+1G>A) has been … (more) The CHEK2 c.444+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant (previously known as IVS2+1G>A) has been reported to be associated with predisposition to hereditary non-polyposis colorectal cancer (Yurgelun et al. 2015. PubMed ID: 25980754), an increased risk of breast and prostate cancer in Eastern European populations, and shows co-segregation with disease with a weakly penetrant effect (Dong et al. 2003. PubMed ID: 12533788; Cybulski et al. 2004. PubMed ID: 15492928; Cybulski et al. 2011. PubMed ID: 21876083; Lhota et al. 2016. PubMed ID: 26822949). It was also reported in patients with essential thrombocythemia diagnosed after age 57 (Janiszewska et al. 2012. PubMed ID: 22058216). This variant is reported in 0.052% of alleles in individuals of European (Finnish) descent in gnomAD. In ClinVar, the vast majority of labs consider this variant pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/128075/). Variants that disrupt the consensus splice donor site in CHEK2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740519.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
not provided (-)	no classification provided Method: phenotyping only	CHEK2-related cancer predisposition Affected status: yes Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749588.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: 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 … (more) 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. (less) Clinical Features: Breast carcinoma (present) Indication for testing: Diagnostic Age: 40-49 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-06-11 Testing laboratory interpretation: Pathogenic
Uncertain significance (-)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: research Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: paternal	Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf Accession: SCV001482300.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021	Family history: no
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Comment:

This c.444+1G>A variant in the CHEK2 gene has been reported in patients with breast cancer [PMID 21876083, 27616075, 26822949, 24713400 referred as IVS2+1G>A]. This variant was also reported in a cohort of patients with thyroid cancer [PMID 25583358], prostate cancer [PMID 12533788] and multiple types of cancer [PMID 15492928]. This variant was also detected in one patient with breast cancer who was compound heterozygous for this c.444+1G>A variant and the p.I157T pathogenic variant [PMID 2471340]. This variant affects the invariant donor splice site of intron 3 of the CHEK2 gene. While not validated for clinical use, computer-based algorithms predict this c.444+1G>A change to disrupt this splicing site. This variant was detected in 14 heterozygous individuals within the ExAC database (http://exac.broadinstitute.org/variant/22-29121230-C-T). This variant is classified as pathogenic.

Comment:

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.

Comment:

Variant summary: The CHEK2 c.444+1G>A variant involves the alteration of a conserved intronic nucleotide that is the first nucleotide of the intron at an exon-intron junction. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a loss of the canonical splice site, which is supported by functional studies that show the use of a cryptic splice site in patient cell lines that introduces 4bp, thus causing a frameshift. A concomitant reduction in CHEK2 protein was also detected in these patient cell lines, supporting the splicing data (Dong_2003). The variant has been identified in numerous patients with breast and prostate cancer (Kraus_2016, Maxwell_2016, Lhota_2016). The variant reportedly identified among BrC patients at a frequency of 1.3% and is considered to be one of the four founder mutations in Poland (Cybulski_2011). This variant was found in 39/278078 control chromosomes at a frequency of 0.0001402, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

The c.444+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the CHEK2 gene. This mutation has been described in numerous breast cancer patients, including individuals with bilateral breast cancer (Kraus C et al. Int. J. Cancer 2017 Jan;140(1):95-102; Pelttari LM et al. Clin. Genet. 2018 Mar;93(3):595-602). In addition, this mutation has been associated with increased risk of breast, prostate, thyroid, and stomach cancers as well as polycythaemia vera in Polish patient cohorts (Cybulski C et al. Am. J. Hum. Genet. 2004 Dec;75:1131-5; Serrano-Fernandez P et al. Breast Cancer Res. Treat. 2009 Sep;117:161-5; Cybulski C et al. J. Clin. Oncol. 2011 Oct;29:3747-52; Teodorczyk U et al. Fam. Cancer. 2013 Sep;12:473-8; Janiszewska H et al. Br. J. Haematol. 2016 Apr;173(1):150-2). Of note, this alteration is also designated as IVS2+1G>A in published literature. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. As such, this alteration is classified as a disease-causing mutation.

Comment:

This variation occurs one base after exon 3 of the CHEK2 gene in a position highly conserved in the human and other genomes that is crucial for mRNA processing. This is expected to result in incorrect splicing and likely results in an absent or disrupted protein product. This variant has been reported in literature in individuals with increased risk for breast, prostate and other cancers (PMID:15492928, PMID: 19030985, PMID:12533788, PMID: 15492928). This variant is also known as IVS2+1G>A in the literature. The mutation database ClinVar contains entries for this variant (Variation ID: 128075). Algorithms developed to predict the effect of single base changes on mRNA splicing suggest that this variant may alter this cellular process. Moreover, experimental studies support the pathogenic effect of this variant through in mRNA splicing (PMID: 12533788).

Comment:

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.

Comment:

This variant causes a G to A nucleotide substitution at the +1 position of intron 3 of the CHEK2 gene. It is also known as CHEK2 IVS2+1G>A in the literature. RNA studies have shown that this variant abolishes the native splice donor site and activates a cryptic splice site, which leads to a frameshift and premature protein truncation (PMID: 12533788, 31843900). This variant has been reported in numerous individuals affected breast cancer (PMID: 15095295, 15492928, 21876083, 24713400, 33030641), ovarian cancer (PMID: 32546565), and prostate cancer (PMID: 12533788, 15087378). A large case-control study has shown that this variant is associated with an increased risk of breast cancer (OR=2.085, 95%CI [1.34 to 3.245], PMID: 33471991). The variant is thought to be a founder mutation in the Polish population (PMID: 15087378, 15492928). This variant has been identified in 40/282678 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 Pathogenic.

Comment:

This sequence change affects a donor splice site in intron 3 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 (rs121908698, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with an increased risk (OR=2.3-3.5) for familial breast cancer or an increased risk (OR=2.5) for prostate cancer (PMID: 15492928, 19030985, 24713400; 21876083 12533788). This variant is also known as IVS2+1G>A. ClinVar contains an entry for this variant (Variation ID: 128075). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 12533788; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Comment:

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25980754, 25583358, 15095295, 27751358, 28918466, 30322717, 30927251, 31159747, 33077847, 32885271, 32338768, 33726816, 21876083, 25525159, 25915596, 26083025, 26250988, 25619955, 26084796, 15492928, 22058216, 19030985, 23296741, 26822949, 27153395, 26629066, 26929905, 26296701, 27038244, 24713400, 12533788, 16914568, 27616075, 27783279, 28727877, 28802053, 15810020, 27488870, 28680382, 28211887, 29356917, 29067458, 17085682, 29520813, 29902706, 29958926, 26681312, 30426508, 31447099, 34308366, 34570182)

Comment:

This variant disrupts a canonical splice-donor site and interferes with normal CHEK2 mRNA splicing. In the published literature, the variant has been reported in individuals and families with hereditary cancer (PMIDs: 28779002 (2017), 25583358 (2015), 24713400 (2014), 21876083 (2011), and 15492928 (2004)). The frequency of this variant in the general population, 0.00052 (13/25122 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

Comment:

The CHEK2 c.444+1G>A variant (rs121908698), also known as IVS2+1G>A, is reported in numerous individuals with familial breast cancer and prostate cancer, and is considered to be one of three CHEK2 founder variants in the Polish population (Bak 2014, Cybulski 2004, Cybulski 2006, Dong 2003). Functional analysis showed that this variant results in a 4-bp insertion due to abnormal splicing and creates a premature termination codon eliminating part of the FHA domain and the entire kinase activation domain of CHEK2 (Dong 2003). This variant is reported in ClinVar (Variation ID: 128075). It is observed in the general population with an overall allele frequency of 0.01% (40/282678 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: Bak A et al. A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland. Hered Cancer Clin Pract. 2014 Apr 8;12(1):10. PMID: 24713400. Cybulski C et al. A novel founder CHEK2 mutation is associated with increased prostate cancer risk. Cancer Res. 2004 Apr 15;64(8):2677-9. PMID: 15087378. Cybulski C et al. CHEK2-positive breast cancers in young Polish women. Clin Cancer Res. 2006 Aug 15;12(16):4832-5. PMID: 16914568. Dong X et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003 Feb;72(2):270-80. PMID: 12533788.

Comment:

The CHEK2 c.444+1G>A variant was identified in 179 of 121122 proband chromosomes (frequency: 0.002) from individuals or families with ascertained in studies of various cancers and was present in 23 of 11230 control chromosomes (frequency: 0.002) from healthy individuals (Bak 2014, Cybulski 2004, Cybulski 2011, Dong 2003, Havranek 2015, Janiszewska 2016, Leedom 2016, Sioek 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs121908698) as With Pathogenic allele, and ClinVar (classified as pathogenic by GeneDx, Ambry Genetics, Invitae, Color Genomics and two clinical laboratories; classified as likely benign by Counsyl). The variant was not identified in Zhejiang Colon Cancer Database. The variant was identified in control databases in 39 of 277022 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: Other in 3 of 6464 chromosomes (freq: 0.001), European Non-Finnish in 24 of 126516 chromosomes (freq: 0.0002), European Finnish in 12 of 25792 chromosomes (freq: 0.001), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The c.444+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. The c.444+1G>A variant was shown to results in a 4-bp insertion due to an abnormal splicing, using an alternative splice donor site in intron 2. This variant eliminates part of forkhead-homology associated domain and the entire kinase activation domain of CHEK2 (Dong 2003, Havranek 2015). In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Comment:

The CHEK2 c.444+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant (previously known as IVS2+1G>A) has been reported to be associated with predisposition to hereditary non-polyposis colorectal cancer (Yurgelun et al. 2015. PubMed ID: 25980754), an increased risk of breast and prostate cancer in Eastern European populations, and shows co-segregation with disease with a weakly penetrant effect (Dong et al. 2003. PubMed ID: 12533788; Cybulski et al. 2004. PubMed ID: 15492928; Cybulski et al. 2011. PubMed ID: 21876083; Lhota et al. 2016. PubMed ID: 26822949). It was also reported in patients with essential thrombocythemia diagnosed after age 57 (Janiszewska et al. 2012. PubMed ID: 22058216). This variant is reported in 0.052% of alleles in individuals of European (Finnish) descent in gnomAD. In ClinVar, the vast majority of labs consider this variant pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/128075/). Variants that disrupt the consensus splice donor site in CHEK2 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

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.

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.
sequence variant affecting splice donor (SO:1000072)			Laboratory Cellgenetics, GMDL Cellgenetics Accession: SCV002578254.1	Publications PubMed (4)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A founder CHEK2 pathogenic variant in association with kidney cancer.	Brooks K	Cancer genetics	2022	PMID: 34992046
Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial.	NICUSeq Study Group	JAMA pediatrics	2021	PMID: 34570182
Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors.	Fiala EM	Nature cancer	2021	PMID: 34308366
Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer.	Nguyen-Dumont T	Cancers	2021	PMID: 33804961
Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients.	Stranneheim H	Genome medicine	2021	PMID: 33726816
Bilateral Disease Common Among Slovenian CHEK2-Positive Breast Cancer Patients.	Nizic-Kos T	Annals of surgical oncology	2021	PMID: 33030641
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
Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer.	Song H	Journal of medical genetics	2021	PMID: 32546565
Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients.	Aoude LG	Scientific reports	2020	PMID: 33077847
Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland.	Wokołorczyk D	International journal of cancer	2020	PMID: 32875559
Rare germline genetic variants and risk of aggressive prostate cancer.	Nguyen-Dumont T	International journal of cancer	2020	PMID: 32338768
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
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: [email protected]	American journal of human genetics	2019	PMID: 31447099
The Landscape of Somatic Genetic Alterations in Breast Cancers from CHEK2 Germline Mutation Carriers.	Mandelker D	JNCI cancer spectrum	2019	PMID: 31360903
High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer.	Bertelsen B	NPJ genomic medicine	2019	PMID: 31263571
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.	Tsaousis GN	BMC cancer	2019	PMID: 31159747
Recurrent moderate-risk mutations in Finnish breast and ovarian cancer patients.	Nurmi A	International journal of cancer	2019	PMID: 30927251
Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors.	AlDubayan SH	JAMA oncology	2019	PMID: 30676620
The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants.	Schubert S	International journal of cancer	2019	PMID: 30426508
Germline pathogenic variants identified in women with ovarian tumors.	Carter NJ	Gynecologic oncology	2018	PMID: 30322717
Clinicopathologic characterization of breast carcinomas in patients with non-BRCA germline mutations: results from a single institution's high-risk population.	Meiss AE	Human pathology	2018	PMID: 29958926
Constitutional mutations of the CHEK2 gene are a risk factor for MDS, but not for de novo AML.	Janiszewska H	Leukemia research	2018	PMID: 29902706
A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer.	Wu Y	The Prostate	2018	PMID: 29520813
Gene-panel testing of breast and ovarian cancer patients identifies a recurrent RAD51C duplication.	Pelttari LM	Clinical genetics	2018	PMID: 28802053
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.	Mandelker D	JAMA	2017	PMID: 28873162
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
Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women.	Walsh T	JAMA oncology	2017	PMID: 28727877
Germline mutations predisposing to diffuse large B-cell lymphoma.	Leeksma OC	Blood cancer journal	2017	PMID: 28211887
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
Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers.	Leedom TP	Cancer genetics	2016	PMID: 27751358
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
Hereditary truncating mutations of DNA repair and other genes in BRCA1/BRCA2/PALB2-negatively tested breast cancer patients.	Lhota F	Clinical genetics	2016	PMID: 26822949
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
The germline mutations of the CHEK2 gene are associated with an increased risk of polycythaemia vera.	Janiszewska H	British journal of haematology	2016	PMID: 26084796
Patterns and functional implications of rare germline variants across 12 cancer types.	Lu C	Nature communications	2015	PMID: 26689913
Rapid Detection Method for the Four Most Common CHEK2 Mutations Based on Melting Profile Analysis.	Borun P	Molecular diagnosis & therapy	2015	PMID: 26446916
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.	Yurgelun MB	Gastroenterology	2015	PMID: 25980754
CHEK2 mutations and the risk of papillary thyroid cancer.	Siołek M	International journal of cancer	2015	PMID: 25583358
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
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
A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland.	Bąk A	Hereditary cancer in clinical practice	2014	PMID: 24713400
The risk of gastric cancer in carriers of CHEK2 mutations.	Teodorczyk U	Familial cancer	2013	PMID: 23296741
A risk of essential thrombocythemia in carriers of constitutional CHEK2 gene mutations.	Janiszewska H	Haematologica	2012	PMID: 22058216
Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer.	Cybulski C	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2011	PMID: 21876083
A simple method of investigating mutations in CHEK2 by DHPLC: a study of the German populations of Saxony, Saxony-Anhalt, and Thuringia.	Scharrer U	Cancer genetics and cytogenetics	2010	PMID: 20417869
Synergistic interaction of variants in CHEK2 and BRCA2 on breast cancer risk.	Serrano-Fernández P	Breast cancer research and treatment	2009	PMID: 19030985
A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer.	Cybulski C	Journal of medical genetics	2006	PMID: 17085682
Association of two mutations in the CHEK2 gene with breast cancer.	Bogdanova N	International journal of cancer	2005	PMID: 15810020
CHEK2 is a multiorgan cancer susceptibility gene.	Cybulski C	American journal of human genetics	2004	PMID: 15492928
Limited relevance of the CHEK2 gene in hereditary breast cancer.	Dufault MR	International journal of cancer	2004	PMID: 15095295
A novel founder CHEK2 mutation is associated with increased prostate cancer risk.	Cybulski C	Cancer research	2004	PMID: 15087378
Mutations in CHEK2 associated with prostate cancer risk.	Dong X	American journal of human genetics	2003	PMID: 12533788
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Text-mined citations for rs121908698 ...

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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908698 ...