rs587780187
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_007194.4(CHEK2):c.613A>T(p.Thr205Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,441,422 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 Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 4.21
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000139 AC: 2AN: 1441422Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 716182
GnomAD4 exome
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2
AN:
1441422
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Cov.:
27
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0
AN XY:
716182
Gnomad4 AFR exome
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Gnomad4 FIN exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
Bravo
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ExAC
AF:
AC:
1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 22419737, 19782031) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 22, 2023 | It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). A yeast based functional study reports that this variant does not alter the protein function (PMID: 33471991 (2016)). 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. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on CHEK2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 05, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 07, 2023 | The p.T205S variant (also known as c.613A>T), located in coding exon 4 of the CHEK2 gene, results from an A to T substitution at nucleotide position 613. The threonine at codon 205 is replaced by serine, an amino acid with similar properties. This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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 20, 2022 | - - |
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.Thr205Ser variant was not identified in the literature nor was it identified in the following databases: Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs587780187) as "With Uncertain significance allele", ClinVar (4x uncertain significance), and the Clinvitae database. The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (Feb 27, 2017). The p.Thr205 residue is conserved in mammals but not in more distantly related organisms. However four out of five 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 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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. - |
Familial cancer of breast Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 23, 2025 | This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 205 of the CHEK2 protein (p.Thr205Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 128084). 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. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (internal data). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;T;T;.;T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
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
N;N;N;N;.;N;.;N;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;.;N;N;N
REVEL
Uncertain
Sift
Benign
T;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;B;.
Vest4
MutPred
Gain of disorder (P = 0.1412);Gain of disorder (P = 0.1412);Gain of disorder (P = 0.1412);Gain of disorder (P = 0.1412);.;Gain of disorder (P = 0.1412);.;Gain of disorder (P = 0.1412);.;
MVP
MPC
0.022
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -7
Find out detailed SpliceAI scores and Pangolin per-transcript scores at