rs77130927
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_007194.4(CHEK2):c.538C>T(p.Arg180Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000828 in 1,613,844 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180H) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00085 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
4
10
5
Clinical Significance
Conservation
PhyloP100: 4.79
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 -4 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.022102207).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.538C>T | p.Arg180Cys | missense_variant | 4/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.538C>T | p.Arg180Cys | missense_variant | 4/15 | 1 | NM_007194.4 | ENSP00000385747 | P2 |
Frequencies
GnomAD3 genomes 0.000619 AC: 94AN: 151932Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00100 AC: 252AN: 251406Hom.: 0 AF XY: 0.00102 AC XY: 139AN XY: 135896
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GnomAD4 exome AF: 0.000850 AC: 1243AN: 1461790Hom.: 0 Cov.: 32 AF XY: 0.000854 AC XY: 621AN XY: 727196
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GnomAD4 genome 0.000618 AC: 94AN: 152054Hom.: 0 Cov.: 32 AF XY: 0.000686 AC XY: 51AN XY: 74310
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:15Benign:12
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4Benign:4
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHEK2 p.Arg180Cys variant was identified in 172 of 93852 proband chromosomes (frequency: 0.002) from individuals or families with hereditary breast and ovarian cancer, prostate cancer and Lynch syndrome and was present in 147 of 89446 control chromosomes (frequency: 0.002) from healthy individuals (Dong 2003, Dufault 2004, Kleibl 2008, Laitman 2007, Mohamad 2015, Mohelnikova Duchonova 2010, Ng 2016, Southey 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs77130927) as “With other allele”, ClinVar (classified as benign by Color Genomics, Ambry Genetics, and Mendelics Analise Genomica; as likely benign by Invitae and Integrated Genetics; and as uncertain significance by GeneDx, Counsyl, and 4 other submitters). The variant was identified in control databases in 261 of 277166 chromosomes at a frequency of 0.0009, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 14 of 24018 chromosomes (freq: 0.0006), Other in 6 of 6468 chromosomes (freq: 0.0009), Latino in 2 of 34420 chromosomes (freq: 0.00006), European (Non-Finnish) in 153 of 126674 chromosomes (freq: 0.001), Ashkenazi Jewish in 2 of 10152 chromosomes (freq: 0.0002), East Asian in 58 of 18866 chromosomes (freq: 0.003), European (Finnish) in 5 of 25788 chromosomes (freq: 0.0002), and South Asian in 21 of 30780 chromosomes (freq: 0.0007). In a functional yeast assay, the response of the p.Arg180Cys CHEK2 variant to DNA damage was found to be decreased to 0.64 of wild type (1.00; Roeb 2012). A large study of the Breast Cancer Association Consortium found an association with breast cancer risk to be 1.33 odds ratio (Southey 2016). The p.Arg180 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | - - |
| 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 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 13, 2022 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 08, 2016 | Variant summary: The CHEK2 c.538C>T (p.Arg180Cys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 168/123378 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0040472 (35/8648). This frequency is about 142 times the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant has been reported in numerous affected individuals in the literature including breast and prostate cancer patients, however no co-segregation and limited co-occurrence data is provided by these studies. In addition, the variant is also reported in unaffected controls in these studies, suggesting the variant is not causitive in these populations. In a yeast-based functional assay, the variant had an intermediate response to DNA damage (Roeb_2012). Multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS while one has classified it as likely benign. Taken together, this variant is classified as likely benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 21, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Case-control studies are inconclusive regarding association with breast cancer (Southy 2016, Decker 2017); Observed in individuals with breast, prostate, or ovarian cancer (Dong 2003, Dufault 2004, Kleibl 2008, Mohelnikova-Duchonova 2010, Le Calvez-Kelm 2011, Liu 2011, Mohamad 2015, Ng 2016, Chirasophon 2017, Xie 2017); Also known as CHEK2 c.667C>T (p.Arg223Cys); Published functional studies are inconclusive: intermediate response to DNA damage (Walsh 2011, Roeb 2012); This variant is associated with the following publications: (PMID: 26757417, 26483394, 28580595, 18085035, 30826992, 31060593, 25629968, 12533788, 22995991, 25980754, 25525159, 15095295, 20643596, 21618645, 24549055, 21244692, 27153395, 27498913, 22419737, 27595995, 21744992, 18058223, 18996005, 27621404, 23960188, 27783279, 22006311, 23555315, 28188963, 28452373, 28779002, 19782031, 29879026, 29470806, 30287823, 30851065, 31050813, 31422574, 29667044, 29263802, 32566746, 32041497, 33326660, 32906215) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 21, 2022 | BS3_supporting - |
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 12, 2023 | - - |
Familial cancer of breast Uncertain:3Benign:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 06, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Oct 07, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| 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, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jul 08, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP6. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 26, 2016 | This alteration is classified as 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 | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jan 16, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 11, 2016 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 09, 2021 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:2Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | research | Cancer Genomics Group, Japanese Foundation For Cancer Research | May 01, 2019 | - - |
| Likely benign, criteria provided, single submitter | research | Molecular Oncology Research Center, Barretos Cancer Hospital | Jan 25, 2024 | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 18, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
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 | Sep 14, 2022 | - - |
CHEK2-related cancer predisposition Uncertain: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. - |
Malignant tumor of prostate Uncertain:1
| Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
CHEK2-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 28, 2023 | 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;D;D;.;D;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;.;.;D;D;.;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;.;M;M;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D;D;D;.;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;.;D;D;.
Sift4G
Uncertain
D;D;D;D;D;.;D;D;D
Polyphen
P;D;P;P;P;P;D;.;.
Vest4
MVP
MPC
0.025
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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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