22-28725242-C-T

Variant names:

• chr22-28725242-C-T
• rs121908698
• NM_007194.4:c.444+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1 PP3 PP5_Very_Strong

The NM_007194.4(CHEK2):​c.444+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000905 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: CHEK2 NM_007194.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:54 U:1 O:1
• Conservation: PhyloP100: 6.03

Genes affected

CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.6, offset of 4, new splice context is: tagGTaatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP3: Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, Dann, MutationTaster was below the threshold]
• PP5: Variant 22-28725242-C-T is Pathogenic according to our data. Variant chr22-28725242-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725242-C-T is described in Lovd as [Pathogenic]. Variant chr22-28725242-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.444+1G>A		splice_donor_variant, intron_variant	Intron 3 of 14	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.444+1G>A		splice_donor_variant, intron_variant	Intron 3 of 14	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251274 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1461812 Hom.: 0 Cov.: 32 AF XY: 0.0000935 AC XY: 68 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.0000971

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74432

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000153 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:54 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:16

Jun 24, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 02, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 24, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHEK2: PVS1, PS4, PM2:Supporting -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 10, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4_moderate, PVS1 -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:16

Jan 24, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 27, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 23, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 25, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 17, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2020

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 12533788; internal data). For these reasons, this variant has been classified as Pathogenic. -

Mar 09, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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]. -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2022

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1, PS3, PS4_STR, BS1 -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2022

Laboratory Cellgenetics, GMDL Cellgenetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Pathogenic:4 Uncertain:1

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Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Feb 04, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PS4 -

Nov 30, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 31, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 multiple individuals diagnosed with 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 polycythemia 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. -

CHEK2-related cancer predisposition Pathogenic:2 Other:1

Sep 21, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, Bąk et al. 2014, Borun et al. 2015, Siołek 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 (Bąk 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. -

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Breast and/or ovarian cancer Pathogenic:2

Jun 16, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CHEK2-related disorder Pathogenic:1

Aug 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Inherited breast cancer and ovarian cancer Pathogenic:1

Oct 29, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1,PM5_Supporting -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C5882668:Li-Fraumeni syndrome 2 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:Li-Fraumeni syndrome 2 Pathogenic:1

May 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and colorectal cancer, susceptibility to Pathogenic:1

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast carcinoma Pathogenic:1

Aug 09, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Li-Fraumeni syndrome 2 Pathogenic:1

Jul 12, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4,PS1_SUP -

Breast cancer, susceptibility to Pathogenic:1

Sep 29, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer Pathogenic:1

Aug 17, 2022

Human Genetics Bochum, Ruhr University Bochum

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used to clasify this variant: PVS1, PM2, PS4 -

Melanoma Pathogenic:1

Dec 05, 2022

Human Genetics Bochum, Ruhr University Bochum

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used to clasify this variant: PVS1, PM2, PS4 -

Familial cancer of breast;C5882668:Li-Fraumeni syndrome 2 Pathogenic:1

Sep 01, 2019

King Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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TUMOR PREDISPOSITION SYNDROME 4, BREAST/PROSTATE Pathogenic:1

Nov 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Malignant tumor of breast Pathogenic:1

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 laboratory’s criteria to be classified as pathogenic. -

Endometrial carcinoma Pathogenic:1

Feb 21, 2023

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	35
DANN	Benign	0.95
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.94		Position offset: -3
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908698; hg19: chr22-29121230; COSMIC: COSV60425482;