rs587782849
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong
The NM_007194.4(CHEK2):c.592+3A>T variant causes a splice donor 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. 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_donor_region, intron
NM_007194.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9976
1
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.592+3A>T | splice_donor_region_variant, intron_variant | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.592+3A>T | splice_donor_region_variant, intron_variant | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251318Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135866
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GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461750Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727188
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:23Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:9
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 22, 2024 | PVS1_strong+PS4_mod+PM2_sup - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 01, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Aug 01, 2023 | This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PP5;PS4;PVS1 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 27, 2023 | The CHEK2 c.592+3A>T variant has been reported in the published literature in in individuals with breast cancer including early age of onset (PMID: 27616075 (2016), 29522266 (2018), 33925588 (2021), 33919281 (2021), 31300551 (2020)) and colorectal cancer (PMID: 27978560 (2016)). 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 (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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | CHEK2: PM2, PS4:Moderate, PP3, PS3:Supporting - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 08, 2023 | Observed in individuals with CHEK2-related cancers and suggested to be a Greek founder variant (PMID: 27616075, 27978560, 29522266, 32658311, 33925588, 35418818, 35264596); 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); 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) - |
Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Familial cancer of breast Pathogenic:6Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2024 | - - |
Uncertain significance, flagged submission | clinical testing | Counsyl | Jun 27, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | May 18, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 08, 2023 | This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad Internal Data]. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | 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 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). 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. The resulting mRNA is expected to undergo nonsense-mediated decay. This variant causes significant reduction of the normal transcript (PMID: 27616075, 31843900, 33925588; Invitae). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Mar 30, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 20, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 14, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 11, 2022 | - - |
CHEK2-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 14, 2024 | 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. - |
Familial cancer of breast;C5882668:Li-Fraumeni syndrome 2 Pathogenic:1
Pathogenic, no assertion criteria provided | research | King Laboratory, University of Washington | Sep 01, 2019 | - - |
Malignant tumor of breast Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 11, 2024 | - - |
Malignant tumor of prostate Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar | - | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 08, 2022 | 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. - |
Breast carcinoma Uncertain:1
Uncertain significance, flagged submission | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 09, 2021 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at