rs587782849

Variant names:

• chr22-28724974-T-A
• rs587782849
• NM_007194.4:c.592+3A>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28724974-T-A
• chr22-28724974-T-C
• chr22-28724974-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_007194.4(CHEK2):​c.592+3A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CHEK2 NM_007194.4 splice_region, intron
• Scores: Splicing: ADA: 0.9976
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26 U:2
• Conservation: PhyloP100: 3.10

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 Likely_pathogenic. Variant got 9 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
• PP5: Variant 22-28724974-T-A is Pathogenic according to our data. Variant chr22-28724974-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28724974-T-A is described in Lovd as [Pathogenic]. Variant chr22-28724974-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.592+3A>T		splice_region_variant, intron_variant	Intron 4 of 14	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.592+3A>T		splice_region_variant, intron_variant	Intron 4 of 14	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152116 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251318 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461750 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

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: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Oct 04, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant demonstrated to result in aberrant splicing leading to a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 27616075, 31843900, 33925588, 37725924); Observed in individuals with CHEK2-related cancers and suggested to be a Greek founder variant (PMID: 38118367, 27616075, 27978560, 29522266, 32658311, 33925588, 35418818, 35264596, 35350808, 35402282, 33980423, 35534704, 38630906, 38313678); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.721+3A>T; This variant is associated with the following publications: (PMID: 27616075, 27978560, 29522266, 32658311, 31843900, 31300551, 34426522, 33925588, 35220195, 35264596, 35418818, 35350808, 37725924, 33919281, 35402282, 33980423, 38630906, 38313678, 38118367, 35534704) -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 22, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_strong+PS4_mod+PM2_sup -

Aug 01, 2023

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PP5;PS4;PVS1 -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHEK2: PM2, PS4:Moderate, PP3, PS3:Supporting -

Mar 14, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHEK2 c.592+3A>T variant has been reported in the published literature in individuals affected with breast cancer (PMID: 27616075 (2016), 29522266 (2018), 33925588 (2021), 33919281 (2021), 31300551 (2020), 35264596 (2022), 38313678 (2024)), colon/colorectal cancer (PMID: 27978560 (2016), 35418818 (2022)), and prostate cancer (PMID: 35350808 (2022)). This variant was reported to result in aberrant splicing and the alternative transcripts are predicted to result in truncated CHEK2 protein (PMID: 27616075 (2016), 33925588 (2021)). However, another study analyzing the fraction of transcripts in a patient carrying this variant found that 55% of transcripts were wild type (PMID: 31843900 (2019)). Hence, the effects of this splicing on CHECK2 protein function are inconclusive. The frequency of this variant in the general population, 0.034 (297/8700 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic. -

Familial cancer of breast Pathogenic:6 Uncertain:1

Mar 30, 2023

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 08, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad Internal Data]. -

Jun 27, 2016

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 4 of the CHEK2 gene. It does not directly change the encoded amino acid sequence of the CHEK2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs587782849, gnomAD 0.005%). This variant has been observed in individual(s) with breast cancer and colorectal cancer (PMID: 27616075, 27978560, 29522266, 32658311, 33919281, 33980423, 35534704). ClinVar contains an entry for this variant (Variation ID: 142956). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4 and skipping of exon 4 and 5, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 27616075, 31843900, 33925588; internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:4

Feb 19, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1 (RNA), PM2_Supporting CHEK2:c.592+3A>T is an intronic variant located close to a canonical splice site. Transcript-based analysis on mRNA extracted from patient's blood lymphoblastoid cells treated with puromycin indicates that this variant results in 3 transcripts involving the skipping of exon 4, skipping of exons 4 and 5, and skipping of exon 5 (r.445_592del, r.445_683del and r.593_683del, respectively) (PMID:31843900)(PVS1_RNA). Also, other mRNA-based assays report the skipping of exon 4, and exons 4 and 5, both resulting in NMD (PMID: 33925588, 27616075). This variant is found in 5/268210 alleles at a frequency of 0.002% in the gnomAD v2.1.1 database, non-cancer dataset (PM2_Supporting) The SpliceAI algorithm predicts the loss of the splice donor site (delta score: 0.9). This variant has been found in multiple cancer-affected individuals (PMID: 33980423, 33925588, 35350808, 33919281, 29522266, 27978560, internal data). It was reported to cosegregate in 2 cancer-affected siblings (PMID: 38313678). And it was found in 5 out of 728 breast cancer- affected individuals and 1 out of 790 healthy controls (PMID: 32658311). This variant has been reported in the ClinVar database (7x pathogenic, 17x likely pathogenic) and in the LOVD database (3x pathogenic, 3x likely pathogenic). Based on currently available information, the variant c.592+3A>T should be considered a likely pathogenic variant according to ACMG/AMP classification guidelines. -

Aug 19, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.592+3A>T intronic variant results from an A to T substitution 3 nucleotides after coding exon 3 in the CHEK2 gene. This alteration has been detected in multiple breast cancer cohorts (Hauke J et al. Cancer Med, 2018 04;7:1349-1358;Fostira F et al. J. Med. Genet., 2020 01;57:53-61; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295; Apostolou P et al. Cancers (Basel), 2021 Apr;13). This alteration was also identified in one patient with colorectal cancer at 39 years of age (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). RNA analysis from a breast cancer patient who carried this variant identified two abnormally spliced transcripts predicted to result nonsense-mediated decay (Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102), and another RNA study demonstrated this alteration has a deleterious splicing impact (Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec). In addition, internal RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Feb 11, 2022

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an A>T nucleotide substitution at the +3 position of intron 4 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies with heterozygous carriers have shown that this variant causes aberrant splicing and causes out-of-frame skipping of exon 4, or exons 4 and 5 (PMID: 27616075, 31843900, 33925588). The observed exon skipping is expected to result in nonsense-mediated decay of the mutant transcripts. An external laboratory has also reported observation of abnormal splicing in multiple carriers based on their internal RNA studies (ClinVar SCV000187541.6). This variant has been reported in over twenty individuals affected with breast cancer (PMID: 27616075, 28486781, 29522266, 31300551, 32658311, 33919281, 33925588, 33980423), colorectal cancer (PMID: 27978560), and prostate cancer (PMID: 35350808). A haplotype analysis has shown a founder effect of this variant for individuals of Greek descent (PMID: 33925588). This variant has also been identified in 8/251318 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. -

CHEK2-related disorder Pathogenic:1

Feb 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHEK2 c.592+3A>T variant is predicted to interfere with splicing. This variant has been reported in individuals with colorectal cancer (Pearlman et al. 2017, eTable 2. PubMed ID: 27978560; Akcay. 2020. PubMed ID: 32658311; Ercoskun and Ozkan. 2022. PubMed ID: 35418818), breast cancer (Table 1, Kraus et al. 2017. PubMed ID: 27616075; reported as c.721+3A>T in Table 3, Bora et al. 2022. PubMed ID: 35220195; Toss et al. 2021. PubMed ID: 33919281; Ece Solmaz et al. 2021. PubMed ID: 33980423), and breast/ovarian cancer (Table S1, Kauke et al. 2018. PubMed ID:29522266). Functional analysis (RT-PCR) has demonstrated the formation of two different shortened CHEK2 transcripts, one lacking exon 4 and the other lacking exons 4-5 (Figure 1, Kraus et al. 2017. PubMed ID: 27616075). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/142956/). In summary, this variant is interpreted as likely pathogenic. -

Li-Fraumeni syndrome 2 Pathogenic:1

Oct 09, 2024

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 4 of the CHEK2 gene. It does not directly change the encoded amino acid sequence of the CHEK2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This nucleotide position is well conserved. Not observed at significant frequency in large population cohorts (gnomAD). This variant has been observed in individual(s) with breast cancer and colorectal cancer (PMID: 27616075, 27978560, 29522266, 32658311, 33919281, 33980423). ClinVar contains an entry for this variant (Variation ID: 142956). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in complex altered splicing including up regulation of naturally occurring isoforms and skipping of exon 4 (also known as exon 3) and skipping of exon 4 and 5, which introduce premature termination codons. This variant causes significant reduction of the normal transcript (PMID: 27616075, 31843900, 33925588). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In summary, this variant has been classified as Likely Pathogenic. Pathogenic/likely pathogenic mutations in the CHEK2 gene cause breast cancer susceptibility (OMIM# 114480). -

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

- -

Malignant tumor of breast Pathogenic:1

May 11, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of prostate Pathogenic:1

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Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Nov 08, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CHEK2 c.592+3A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5 prime splicing donor site, while two predict the variant weakens the 5 prime donor site. At least two publications report experimental evidence that this variant affects mRNA splicing, leading to the skipping of exon 4 and exon 4/5, both predicted to cause a frameshift (e.g. Kraus_2016, Casadei_2019). The variant allele was found at a frequency of 3.6e-05 in 252298 control chromosomes (gnomAD and Akcay_2021). c.592+3A>T has been reported in the literature in multiple individuals affected with breast and/or ovarian cancer, some of these cases were diagnosed at an early age and/or indicated to have a positive family history and several patients were comprehensively genotyped on large cancer gene panels (e.g. Kraus_2016, Lolas Hamameh_2017, Hauke_2018, Fostria_2020, Akcay_2021, Toss_2021, Bora_2022). These reports indicate that the variant is likely associated with Hereditary Breast and Ovarian Cancer, however it should be considered that familial co-segregation data has, to our knowledge, yet to be reported. BLAT searches for the intronic sequence surrounding the variant (30 nucleotide sequence surrounding the location of the variant) gave only 1 hit with 100% sequence identity on chromosome 22 (i.e. at the expected location). Therefore, the variant is unlikely to be derived from a CHEK2 pseudogene. Fourteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Eight classified the variant as likely pathogenic (n=7)/pathogenic (n=1), and six classified it as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

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Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3+PS4+PP4 -

Breast carcinoma Uncertain:1

Aug 09, 2021

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.2
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.63
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.90		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs587782849; hg19: chr22-29120962;