rs587780180
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_007194.4(CHEK2):c.1556G>T(p.Arg519Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,595,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: -0.470
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 -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.04390779).
BP6
Variant 22-28687973-C-A is Benign according to our data. Variant chr22-28687973-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128066.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=19}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.1556G>T | p.Arg519Leu | missense_variant | 15/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.1556G>T | p.Arg519Leu | missense_variant | 15/15 | 1 | NM_007194.4 | ENSP00000385747 | P2 |
Frequencies
GnomAD3 genomes 0.000118 AC: 18AN: 152112Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000223 AC: 52AN: 233042Hom.: 0 AF XY: 0.000211 AC XY: 27AN XY: 128160
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GnomAD4 exome AF: 0.000130 AC: 187AN: 1443708Hom.: 0 Cov.: 30 AF XY: 0.000129 AC XY: 93AN XY: 718620
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GnomAD4 genome 0.000118 AC: 18AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12AN XY: 74298
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:24Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:8Benign:1
| Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 16, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 03, 2023 | In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 29470806 (2016), 32658311 (2021), 32906215 (2020), 30303537 (2019), 31159747 (2019), and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2)) and renal cell carcinoma (PMID: 35441217 (2022)), as well as healthy individuals (PMIDs: 21244692 (2011) and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2)). The frequency of this variant in the general population, 0.00017 (21/123898 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| 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 | GeneDx | Jul 02, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon, breast, ovarian, and other cancers, as well as in control groups (PMID: 29470806, 31780696, 30303537, 31206626, 32658311, 32283892, 35402282, 35264596, 35441217); Published functional studies are inconclusive: intermediate growth rate in response to DNA damage (PMID: 30851065); This variant is associated with the following publications: (PMID: 31422574, 24879340, 21244692, 26787654, 28102005, 28166811, 29470806, 31159747, 30303537, 31780696, 32283892, 32906215, 32659967, 35264596, 35441217, 32658311, 31206626, 35402282, 35127508, 29522266, 28779002, 22419737, 37306523, 34326862, 35534704, 35980532, 30851065) - |
| Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | CHEK2: BP4, BS3:Supporting - |
Familial cancer of breast Uncertain:5Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Apr 01, 2019 | To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an allele frequency of 0.000026 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/). Thus, it is unknown at this time whether this variant increases cancer risk. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 519 of the CHEK2 protein (p.Arg519Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29470806, 32658311). ClinVar contains an entry for this variant (Variation ID: 128066). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 05, 2023 | This sequence change replaces arginine with leucine at codon 519 of the CHEK2 protein (p.Arg519Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs587780180, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 128066) by multiple clinical diagnostic laboratories after 2014 classify this variant as uncertain significant variant .In addition, this alteration is predicted to be tolerated by in silico analysis. This variant has been reported to have conflicting or insufficient data to determine the effect on CHEK2 protein function (PMID: 30851065). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 01, 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]. - |
Hereditary cancer-predisposing syndrome Uncertain:3Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 14, 2023 | This missense variant replaces arginine with leucine at codon 519 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown this variant to result in a partial loss of CHEK2 DNA damage repair activity in a yeast-based assay (PMID: 30851065) and normal kinase activity in an in vitro assay (PMID: 31780696). This variant has been reported in individuals affected with breast cancer (PMID: 29470806, 31780696, 35402282), ovarian cancer (PMID: 32546565), as well as in unaffected control individuals (PMID: 21244692, 32546565). In a large breast cancer case-control study, this variant has been observed in 13/60453 cases and 7/53454 controls (OR=1.642, 95%CI 0.655 to 4.116, p-value=0.3720; PMID: 33471991). This variant has been identified in 54/264444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Aug 14, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 16, 2024 | 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. - |
not specified Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 26, 2021 | Variant summary: CHEK2 c.1556G>T (p.Arg519Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 235260 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Breast Cancer (0.00023 vs 0.00031), allowing no conclusion about variant significance. c.1556G>T has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with Breast and/or Lynch associated tumors/colorectal cancer (example, Singh_2018, Young_2016, Weitzel_2019, deCarvalho_2020, Vargas-Parra_2020, Ackay_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on protein function (Delimitsou_2019). The most pronounced variant effect results in intermediate levels of normal activity evaluating MMS (methyl-methanesulfonate) induced DNA damage repair in a yeast based functional assay. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 27, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
CHEK2-related disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 25, 2023 | The CHEK2 c.1556G>T variant is predicted to result in the amino acid substitution p.Arg519Leu. This variant has been identified in individuals with breast and/or ovarian cancer (Table S1, Young et al. 2016. PubMed ID: 26787654; Table S5, Decker et al. 2017. PubMed ID: 28779002; Table S1, Hauke et al. 2018. PubMed ID: 29522266; Table S4, Singh et al. 2018. PubMed ID: 29470806; Table S6, Akcay et al. 2020. PubMed ID: 32658311), individuals with a personal and/or family history of hereditary cancer (Table S6, Tsaousis et al. 2019. PubMed ID: 31159747; Table 2, Dutil et al. 2019. PubMed ID: 31780696; Table S1, Vargas-Parra et al. 2020. PubMed ID: 32906215), an individual with colorectal cancer (Table 2, Erdem et al. 2020. PubMed ID: 32283892), as well as in a control individual (Table S1, Le Calvez-Kelm et al. 2011. PubMed ID: 21244692). The results of in vitro and in vivo experimental studies of this variant are inconclusive (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065; Dutil et al. 2019. PubMed ID: 31780696). This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29083961-C-A) and is interpreted as uncertain significance by the vast majority of clinical laboratories in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/128066/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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 | May 05, 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 | - - |
Predisposition to cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jul 13, 2022 | The CHEK2 c.1556G>T (p.Arg519Leu) missense change has a maximum subpopulation frequency of 0.046% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has been reported in individuals with breast and/or ovarian cancer, colorectal cancer, and Lynch syndrome (PMID: 29470806, 29522266, 30303537, 31780696, 32283892, 32659967, 34130653, 35127508, 35402282). The in silico tool REVEL predicts a benign effect on protein function, and functional studies are inconclusive. This variant was characterized as semi-functional (intermediate) in a yeast-based assay evaluating DNA damage response (PMID: 30851065), whereas kinase activity and phosphorylation in a transfected cell line was comparable to the wild-type (PMID: 31780696). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHEK2 p.Arg519Leu variant was not identified in the literature however alternate substitutions at the same amino acid position (R519Q/R519G) were identified in epithelial ovarian cancers and these amino acid substitutions were localized to the nuclear localization signal region; it is suggested that mutations in this region could adversely affect the nuclear import of CHEK2, reduce the protein level of effective and functional CHEK2, and impact CHEK2 associated repair pathways (Ow 2014). The variant was also identified in dbSNP (ID: rs587780180) “With Uncertain significance” allele, and ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Counsyl, and Color Genomics Inc). The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. Although the p.Arg519 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Leu variant may impact the protein. 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. - |
Hereditary cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.;T;.;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
.;T;.;T;.;T;T;T;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L;.;L;.;L;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;.;D;D;.;D;D
REVEL
Benign
Sift
Uncertain
D;D;D;.;D;D;.;D;D
Sift4G
Uncertain
D;D;D;.;D;D;.;D;D
Polyphen
P;B;P;.;P;P;P;P;B
Vest4
MutPred
Loss of MoRF binding (P = 0.0687);.;Loss of MoRF binding (P = 0.0687);.;Loss of MoRF binding (P = 0.0687);.;Loss of MoRF binding (P = 0.0687);.;.;
MVP
MPC
0.044
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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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