rs587782268
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_007194.4(CHEK2):c.1053G>T(p.Glu351Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,522 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000068 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 0.561
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 0 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.1053G>T | p.Glu351Asp | missense_variant | 10/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.1053G>T | p.Glu351Asp | missense_variant | 10/15 | 1 | NM_007194.4 | ENSP00000385747.1 |
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251292Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135824
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GnomAD4 exome AF: 0.0000684 AC: 100AN: 1461376Hom.: 0 Cov.: 30 AF XY: 0.0000894 AC XY: 65AN XY: 727024
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GnomAD4 genome 0.0000329 AC: 5AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74308
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:15Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:7
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 05, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal history of breast cancer, colorectal cancer, or other cancers, but also in unaffected controls (PMID: 26580448, 28779002, 31159747, 32658311, 36200007, 37449874); Also known as c.1182G>T, p.(E394D); This variant is associated with the following publications: (PMID: 27149842, 21244692, 28423702, 31159747, elebi2022[article], 36200007, 28779002, 26580448, 32658311, 22419737, 19782031, 38734904, 37449874, 34903604) - |
| 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 | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 03, 2024 | The CHEK2 c.1053G>T (p.Glu351Asp) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMID: 32658311 (2021), 31159747 (2019)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). A published functional study reports that this variant did not impact CHEK2 autophosphorylation but impaired kinase activity (PMID: 34903604 (2021)) and another study reported this variant as functionally impaired based on KAP1 phosphorylation and CHEK2 autophosphorylation (PMID: 37449874 (2023)). The frequency of this variant in the general population (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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| 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+ | - | - - |
Familial cancer of breast Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 351 of the CHEK2 protein (p.Glu351Asp). This variant is present in population databases (rs587782268, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of CHEK2-related condtions (PMID: 31159747; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142151). 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 disruptive. 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 | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 05, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 351 of the CHEK2 protein (p.Glu351Asp). This variant is present in population databases (rs587782268, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of CHEK2-related condtions (PMID: 27149842, 21244692, 28423702, 32658311, 34903604, 31159747, 19782031, 22419737). ClinVar contains an entry for this variant (Variation ID: 142151). In silico analysis supports that this missense variant has a deleterious effect on protein structure/function. 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 06, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 24, 2023 | The p.E351D variant (also known as c.1053G>T), located in coding exon 9 of the CHEK2 gene, results from a G to T substitution at nucleotide position 1053. The glutamic acid at codon 351 is replaced by aspartic acid, an amino acid with highly similar properties. This variant has been identified in numerous disease cohorts as well as unaffected control groups across studies (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Decker B et al. J Med Genet, 2017 11;54:732-741; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Akcay IM et al. Int J Cancer, 2021 01;148:285-295; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration was reported as damaging in an mES cell-based assay of CHEK2 activity (Boonen RACM et al. Cancer Res, 2022 Feb;82:615-631). This alteration was also reported as functionally impaired in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 17, 2022 | This missense variant replaces glutamic acid with aspartic acid at codon 351 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). This variant has been reported as defective for phosphorylation of the CHEK2 substrate KAP1, but not CHEK2 threonine-183 autophosphorylation in a mouse embryonic stem cell based assay (PMID: 34903604). This variant has been reported in individuals affected with breast cancer and colorectal cancer (PMID: 32658311, 31159747). This variant has also been identified in 22/251292 chromosomes (18/30608 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). In a large breast cancer case-control study, this variant was observed in 10/60466 cases and 2/53461 unaffected controls; OR=4.421, 95%CI 0.969 to 20.18, p-value=0.043 (Leiden Open Variation Database DB-ID CHEK2_000058; PMID: 33471991). 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 | GeneKor MSA | Aug 01, 2018 | - - |
Li-Fraumeni syndrome 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 21, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
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.Glu351Asp variant was not identified in the literature nor was it identified in the MutDB or Zhejiang University databases. The variant was identified in dbSNP (ID: rs587782268) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx, and Color Genomics), Cosmic (2x in large intestine or endometrium tissue), and in LOVD 3.0 (1x likely benign). The variant was identified in control databases in 22 of 246082 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 4 of 111582 chromosomes (freq: 0.00004), and South Asian in 18 of 30780 chromosomes (freq: 0.0006), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Glu351 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 cancer predisposition Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 11-05-2020 by 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T;.;T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D;.;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;L;.;L;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;D;D;.;N;N;.
REVEL
Benign
Sift
Pathogenic
D;D;.;D;T;.;T;T;.
Sift4G
Benign
T;T;.;T;T;.;D;D;.
Polyphen
P;P;.;P;D;P;D;.;.
Vest4
MutPred
Loss of methylation at K349 (P = 0.113);Loss of methylation at K349 (P = 0.113);.;Loss of methylation at K349 (P = 0.113);.;Loss of methylation at K349 (P = 0.113);.;.;.;
MVP
MPC
0.16
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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