22-28725027-C-T
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM5BP4_ModerateBP6
The NM_007194.4(CHEK2):c.542G>A(p.Arg181His) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,613,934 control chromosomes in the GnomAD database, including 1 homozygotes. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R181C) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000052 ( 1 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 3.74
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 -1 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr22-28725028-G-A is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.07827735).
BP6
Variant 22-28725027-C-T is Benign according to our data. Variant chr22-28725027-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5598.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=10, not_provided=1}. Variant chr22-28725027-C-T is described in Lovd as [Benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.542G>A | p.Arg181His | 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.542G>A | p.Arg181His | missense_variant | 4/15 | 1 | NM_007194.4 | ENSP00000385747.1 |
Frequencies
GnomAD3 genomes 0.0000592 AC: 9AN: 152048Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000135 AC: 34AN: 251408Hom.: 1 AF XY: 0.000125 AC XY: 17AN XY: 135894
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GnomAD4 exome AF: 0.0000520 AC: 76AN: 1461764Hom.: 1 Cov.: 32 AF XY: 0.0000660 AC XY: 48AN XY: 727186
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GnomAD4 genome 0.0000591 AC: 9AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74386
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:11Benign:8Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial cancer of breast Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 09, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 28, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 181 of the CHEK2 protein (p.Arg181His). This variant is present in population databases (rs121908701, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with thyroid cancer, prostate cancer, neuroblastoma, breast cancer, Hodgkin lymphoma, and non-Hodgkin lymphoma (PMID: 12533788, 15095295, 21744992, 23334666, 26506619, 30826992). ClinVar contains an entry for this variant (Variation ID: 5598). 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 have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065, 31050813, 34903604). 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. - |
not provided Uncertain:1Benign:2Other:1
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 20, 2019 | - - |
| not provided, no classification provided | literature only | Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 29700634, 31118792, 21744992, 15095295, 12533788, 23334666, 26506619, 28055978, 27720647, 28418444, 16982735, 22419737, 30067863, 21059199, 16835864, 29752822, 28580595, 30851065, 31050813, 30287823, 29520813, 31056747, 32906215) - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 25, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 30, 2022 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 17, 2021 | - - |
not specified Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 30, 2023 | Variant summary: CHEK2 c.542G>A (p.Arg181His) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 360012 control chromosomes (gnomAD and jMorp (Tadaka_2021) databases), predominantly at a frequency of 0.0013 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.542G>A has been reported in the literature in Japanese case control studies of individuals with breast cancer or colorectal cancer with no reported association (e.g., Momozawa_2018, Fujita_2022), as well as in individuals affected with Hodgkins lymphoma, Non-Hodgkins lymphoma, sporadic prostate cancer, or Neuroblastoma, and at-least one individual with breast cancer from a family testing negative for mutations in BRCA1 and 2 genes (e.g., Havranek_2011, Havranek_2015, Dong_2003, Pugh_2013, Dufault_2004). These reports do not provide unequivocal conclusions about the association of this variant with any of these cancers and some even cite this in the context of a neutral variant (e.g., Havranek_2011) or a non-significant association (e.g., Dufault_2004). At least three recent publications report experimental evidence evaluating an impact on protein function. The studies showed no damaging effect of this variant using an in-vivo yeast based assay evaluating the ability to repair MMS (methylmethanesulfonate) induced DNA damage (e.g., Delimitsou_2019) and cell-based assays quantifying KAP1-S473 phosphorylation (e.g., Kleibova_2019, Boonen_2022). The following publications have been ascertained in the context of this evaluation (PMID: 35643632, 30851065, 33309985, 21744992, 31050813, 30287823, 23334666, 33179747). Multiple ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments (VUS, n = 11; likely benign, n = 4). Some of these submitters list overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Malignant tumor of prostate Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2003 | - - |
Li-Fraumeni syndrome 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 28, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
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 | Oct 31, 2018 | - - |
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.Arg181His variant was identified in 4 of 3908 proband chromosomes (frequency: 0.001) from individuals with non-hodgkins lymphoma, neuroblastoma, breast and prostate cancer and was not identified in 2736 control chromosomes from healthy individuals (Dong 2003,Pugh 2013, Dufault 2004, Havranek 2015). The variant was identified in dbSNP (rs121908701) as “with pathogenic allele”, in ClinVar (interpreted as "uncertain significance" by Invitae, Color and 6 others, "pathogenic" by OMIM and not provided 1 other). The variant was identified in control databases in 34 of 277,176 chromosomes (1 homozygous) at a frequency of 0.0001 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 1 of 24,026 chromosomes (freq: 0.00004), Latino in 1 of 34,420 chromosomes (freq: 0.00003), European in 3 of 126,676 chromosomes (freq: 0.00002), East Asian in 25 of 18,864 chromosomes (freq: 0.001), and South Asian in 4 of 30,782 chromosomes (freq: 0.0001). The variant was not observed in the Other, Ashkenazi Jewish and Finnish, populations. The variant is located within the Forkhead Associate Domain, but further studies are required to determine if it affects protein function. The p.Arg181His residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Cancer Genomics Group, Japanese Foundation For Cancer Research | May 01, 2019 | - - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 23, 2022 | - - |
Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:Li-Fraumeni syndrome 2 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 08, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;T;T;.;T;.;.;T
Eigen
Benign
Eigen_PC
Benign
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
Benign
T
MutationAssessor
Benign
L;L;L;L;.;L;L;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;.;N;N;.
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;.;T;T;.
Sift4G
Benign
T;T;T;T;T;.;T;T;T
Polyphen
B;B;B;B;B;B;B;.;.
Vest4
MVP
MPC
0.022
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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