rs200050883
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting
The NM_007194.4(CHEK2):c.1312G>T(p.Asp438Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000376 in 1,613,498 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00037 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00038 ( 2 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
1
11
7
Clinical Significance
Conservation
PhyloP100: 4.62
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_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.045587093).
BP6
Variant 22-28695190-C-A is Benign according to our data. Variant chr22-28695190-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128056.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=13, not_provided=2}.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.1312G>T | p.Asp438Tyr | missense_variant | 12/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.1312G>T | p.Asp438Tyr | missense_variant | 12/15 | 1 | NM_007194.4 | ENSP00000385747.1 |
Frequencies
GnomAD3 genomes 0.000375 AC: 57AN: 152144Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000386 AC: 97AN: 251038Hom.: 0 AF XY: 0.000339 AC XY: 46AN XY: 135660
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GnomAD4 exome AF: 0.000376 AC: 549AN: 1461236Hom.: 2 Cov.: 30 AF XY: 0.000359 AC XY: 261AN XY: 726952
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GnomAD4 genome 0.000374 AC: 57AN: 152262Hom.: 1 Cov.: 32 AF XY: 0.000403 AC XY: 30AN XY: 74442
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:21Benign:11Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:9Benign:2Other:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2023 | Published functional studies are inconclusive/conflicting: demonstrates intermediate/reduced kinase activity in some studies while others, including a human-cell based assay, show activity comparable to wildtype (Bell et al., 2007; Delimitsou et al., 2019; Kleiblova et al., 2019; Boonen et al., 2022); Observed in individuals with a personal and/or family history of breast, prostate, or colorectal cancer (Seppala et al., 2003; Bell et al., 2007; Tischkowitz et al., 2008; Baloch et al., 2014; Tung et al., 2015; Kayser et al., 2018; Fanale et al., 2020; Grasel et al., 2020; Moradian et al., 2021; Paduano et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14612911, 15087378, 28828701, 28776603, 28873162, 24390236, 17721994, 18571837, 23960188, 21244692, 27067391, 26787654, 28553140, 25186627, 27153395, 27498913, 27878467, 28452373, 19768534, 29335925, 27595995, 27443514, 29987844, 29484706, 30344923, 28301460, 30851065, 29875428, 29522266, 31050813, 31398194, 31159747, 28779002, 31220302, 33134171, 33322746, 32854451, 33558524, 27009842, 32906215, 30613976, 27535533, 34903604, 34347074, 22419737, 19782031, 35886069, 33840814) - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | The variant was identified in multiple GenomeConnect participants. Variant interpreted as Uncertain significance and reported on 03-29-2018 by Lab or GTR ID Northwell Health Laboratories. Variant interpreted as Uncertain significance and reported, most recently, on 12/04/2018 by GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 14, 2023 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 01, 2023 | In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 36653541 (2023), 35886069 (2022), 33558524 (2021), 33134171 (2020), 31050813 (2019), 29484706 (2018), 29335925 (2018), 28779002 (2017), 25186627 (2015), 24390236 (2014), 21244692 (2011)), endometrial cancer (PMID:27443514 (2016)), colorectal cancer (PMID: 29987844 (2018)), and prostate cancer (PMIDs: 18571837 (2008), 17721994 (2007), 14612911 (2003)). This variant has also been identified in healthy control individuals (PMIDs: 36653541 (2023), 31050813 (2019), 30303537 (2019), 28779002 (2017), 21244692 (2011), 17721994 (2007)), and reported to co-occur with deleterious variants in the MRE11 and MSH2 genes (PMIDs: 33134171 (2020), 27443514 (2016)). Case-control studies suggest this variant is associated with prostate cancer risk but not breast cancer risk (PMIDs: 27595995 (2016), 36653541 (2023)). In addition, experimental studies indicate this variant has neutral to intermediate effects on CHEK2 protein function (PMIDs: 34903604 (2022), 31050813 (2019), 30851065 (2019), 17721994 (2007)). The frequency of this variant in the general population, 0.0013 (32/25122 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | CHEK2: BP1, BP4, BS2 - |
Familial cancer of breast Uncertain:2Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Likely benign, criteria provided, single submitter | research | Research Unit of Translational Medicine, University of Oulu | Nov 22, 2022 | The frequency of p.Asp438Tyr variant in CHEK2 among Northern Finnish breast cancer cases was 0.6% (14/2284) and nearly equal in geographically matched healthy population controls (0.8%, 10/1299) in a study by Kumpula et al. (2023). Similar carrier frequencies in the studied cases and the general population argue against association of CHEK2 p.Asp438Tyr with increased breast cancer risk. Therefore the variant can be classified as likely benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 12, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 09, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
| Uncertain significance, no assertion criteria provided | research | Center of Medical Genetics and Primary Health Care | Apr 08, 2020 | ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: Pkinase domain (M265-529L aa) which contains the catalytic function of protein kinases. Hot-spot has 21 non-VUS coding variants (7 pathogenic and 14 benign), pathogenicity = 33.3%, proximity score 3.967 > threshold 2.472. PP1 Pathogenic Supporting: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PP2 Pathogenic Supporting: 30 out of 48 non-VUS missense variants in gene CHEK2 are pathogenic = 62.5% > threshold of 51.0%, and 308 out of 1,604 clinically reported variants in gene CHEK2 are pathogenic = 19.2% > threshold of 12.0%. PP1 Pathogenic Supporting: 2 patients are sibs (sisters) who share the same variant. BP4 Benign Supporting: 6 benign predictions from DEOGEN2, EIGEN, MVP, MutationAssessor, PrimateAI and REVEL vs 5 pathogenic predictions from DANN, FATHMM-MKL, M-CAP, MutationTaster and SIFT and the position is not conserved." Therefore, this variant was classified as a Variant of Unknown Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 14, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
| Uncertain significance, criteria provided, single submitter | research | Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 30, 2019 | - - |
not specified Uncertain:2Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 28, 2023 | Variant summary: CHEK2 c.1312G>T (p.Asp438Tyr) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 261860 control chromosomes, predominantly at a frequency of 0.00046 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5- fold the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, the frequency in gnomAD and the cases reported in the literature may not be accurate due to the sequencing technology used being unable to distinguish between CHEK2 and its multiple overlapping pseudogenes. This variant has also been reported among 7 women older than 70 years who have never had cancer as reported in the FLOSSIES database. c.1312G>T, has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer, but also in controls and in a family where it did not segregate with disease (examples- Baloch_2013, Bell_2007, LeCalvez-Kelm_2011, Seppala_2003, Tischkowitz_2008, Young_2016, Yadav_2016, Tung_2015, Maxwell_2016, Fostira_2018, Scarpetta_2019). Case control approaches indicated no significant risk association for breast cancer, but a slightly elevated risk for prostate cancer (Le Calvez-Kelm_2011, Southey_2016). These data thus do not allow any conclusion about variant significance. At-least one co-occurrence with another pathogenic variant has been reported (MSH2 c.1697del, p.Asn566IlefsX24), providing supporting evidence for a benign role (Ring_2016). In a mammalian cell based kinase-assay the variant protein showed about 70% reduction in activity (Bell_2007), whereas in a yeast based DNA-damage assay the variant showed similar function to the wild type supporting a benign outcome (Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 24390236, 17721994, 15087378, 30851065, 31811167, 29335925, 30303537, 33134171, 29484706, 25231023, 29987844, 21244692, 30322893, 27153395, 33558524, 27443514, 31512090, 14612911, 27595995, 18571837, 31159747, 25186627, 29875428, 27878467, 31214250, 26787654, 28828701, 23960188). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as uncertain significance (n=15) and likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 11, 2019 | - - |
CHEK2-related cancer predisposition Uncertain:1Other:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Likely benign and reported on 04-04-2017 by Lab 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 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 27, 2023 | - - |
Familial cancer of breast;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C5882668:Li-Fraumeni syndrome 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | curation | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Jan 09, 2024 | Results from functional assays as well as predictions are contradictory. According to the ACMG standard criteria we chose this criterium: BS1 (strong benign): gnomAD v3.1.2 (non-cancer): AF: 0.0005092 + 1 x hom - |
Li-Fraumeni syndrome 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 12, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Carcinoma of colon Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHEK2 p.Asp438Tyr variant was identified in 4 of 1332 proband chromosomes (frequency: 0.003) from Pakistani, Finnish, Polish and Ashkenazi Jewish individuals or families with breast, early onset breast and prostate, or hereditary prostate cancer and was not identified in 590 control chromosomes from healthy individuals (Baloch 2014, Seppala 2003, Tischkowitz 2008, Bell 2007). The variant was identified in dbSNP (ID: rs200050883) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Counsyl, and Color Genomics), and the Zhejiang Colon Cancer Database (14x, co-occurring with CHEK2 c.1100delC). The variant was not identified in Cosmic. The variant was identified in control databases in 108 of 276806 chromosomes at a frequency of 0.0004 (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations: European in 57 of 126326 chromosomes (frequency: 0.0005), Finnish in 33 of 25792 chromosomes (frequency: 0.001), African in 3 of 24032 chromosomes (frequency: 0.0001), Other in 4 of 6456 chromosomes (frequency: 0.0006), Latino in 2 of 34404 chromosomes (frequency: 0.00006), and South Asian in 9 of 30776 chromosomes (frequency: 0.0003). The variant occurs in the catalytic domain of the CHEK2 protein and in vitro analysis of kinase activity showed the variant had a 70% decrease in activity compared to wildtype (Baloch 2014, Bell 2007). The p.Asp438 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Tyr variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
CHEK2-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 28, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hereditary cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Malignant tumor of breast Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Center of Medical Genetics and Primary Health Care | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
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AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.;T;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;.;D;.;D;D;D;.
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L;.;L;.;L;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;.;D;D;.;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;.;D;D;.;D;D
Sift4G
Uncertain
D;D;D;.;D;D;.;D;D
Polyphen
D;D;D;.;D;P;D;D;D
Vest4
MVP
MPC
0.15
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at