rs760449049
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_007194.4(CHEK2):c.1076A>G(p.Glu359Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 3.45
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.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1871323).
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251266Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135828
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GnomAD4 exome AF: 0.00000343 AC: 5AN: 1459086Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2AN XY: 726122
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33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 29, 2021 | DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.1076A>G, in exon 10 that results in an amino acid change, p.Glu359Gly. This sequence change has been described in the gnomAD database in two individuals which corresponds to a population frequency of 0.0018 % (dbSNP rs760449049). The p.Glu359Gly change affects a moderately conserved amino acid residue located in a domain of the CHEK2 protein that is known to be functional. The p.Glu359Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with CHEK2-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu359Gly change remains unknown at this time. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 13, 2024 | Variant summary: CHEK2 c.1076A>G (p.Glu359Gly) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) 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 8e-06 in 251266 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1076A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome as well as healthy controls (e.g., Yurgelun_2015, Decker_2017, Stolarova_2023). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on kinase activity (e.g., Stolarova_2023). The following publications have been ascertained in the context of this evaluation (PMID: 37449874, 25980754, 28779002). ClinVar contains an entry for this variant (Variation ID: 233678). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
not provided Uncertain:2
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHEK2 p.Glu359Gly variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs760449049) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics, and Color). The variant was not identified in the Cosmic, MutDB, Zhejiang University database, the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Glu359 residue is not 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 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 | GeneDx | Jun 09, 2024 | Observed in individuals with breast cancer or a Lynch syndrome-related cancer and/or polyps (PMID: 25980754, 37449874); Published functional studies demonstrate KAP1 phosphorylation and CHK2 auto-phosphorylation comparable to wild-type (PMID: 37449874); RNA studies demonstrate aberrant splicing resulting in both in-frame and out-of-frame transcripts (PMID: 38332730); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25980754, 28576879, 28779002, 30262796, 22419737, 19782031, 33471991, 35451682, 37449874, 38332730) - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 10, 2023 | This missense variant replaces glutamic acid with glycine at codon 359 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 25980754) and in two unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000369). This variant has been identified in 2/251266 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 | Ambry Genetics | Oct 31, 2023 | The p.E359G variant (also known as c.1076A>G), located in coding exon 9 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1076. The glutamic acid at codon 359 is replaced by glycine, an amino acid with similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This alteration has also been reported in at least one breast cancer patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741).This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Familial cancer of breast Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 10, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 359 of the CHEK2 protein (p.Glu359Gly). This variant is present in population databases (rs760449049, gnomAD 0.002%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 233678). 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. 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 | Jan 20, 2024 | - - |
Li-Fraumeni syndrome 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Sep 09, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and nonpolar, at codon 359 of the CHEK2 protein (p.Glu359Gly)This amino acid position is poorly conserved (PhyloP=3.45) . This variant is present in population databases (rs760449049, gnomAD 0.002%). This missense change has been observed in individual(s) with Lynch syndrome PMID: 25980754, 28576879, 28779002, 30262796, 22419737, 19782031, 33471991, 35451682, 37449874, 38332730). ClinVar contains an entry for this variant (Variation ID: 233678). In addition, this alteration is predicted to be tolerated by in silico analysis. 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.Pathogenic/likely pathogenic mutations in the CHEK2 gene cause susceptibility to breast cancer (OMIM# 114480). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
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;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;.;N;.;N;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;.;D;D;.;D;D
REVEL
Benign
Sift
Benign
D;D;.;D;D;.;D;D
Sift4G
Benign
T;T;.;T;T;.;T;T
Polyphen
B;B;.;B;B;B;P;.
Vest4
MutPred
Loss of solvent accessibility (P = 0.0387);Loss of solvent accessibility (P = 0.0387);.;Loss of solvent accessibility (P = 0.0387);.;Loss of solvent accessibility (P = 0.0387);.;.;
MVP
MPC
0.030
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at