rs121908710
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_007194.4(CHEK2):c.*7T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,593,510 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 1 hom. )
Consequence
CHEK2
NM_007194.4 3_prime_UTR
NM_007194.4 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.58
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 -5 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
?
Variant 22-28687890-A-G is Benign according to our data. Variant chr22-28687890-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132820.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4, not_provided=1, Benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.*7T>C | 3_prime_UTR_variant | 15/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.*7T>C | 3_prime_UTR_variant | 15/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000167 AC: 39AN: 233610Hom.: 1 AF XY: 0.000171 AC XY: 22AN XY: 128306
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GnomAD4 exome AF: 0.000112 AC: 162AN: 1441330Hom.: 1 Cov.: 30 AF XY: 0.000111 AC XY: 80AN XY: 717598
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:5Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial cancer of breast Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 18, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2015 | This sequence change falls in the 3'UTR of the CHEK2 gene. It does not change the encoded amino acid sequence of the CHEK2 protein. This variant is present in population databases (rs121908710, 0.02%) and has been reported in the literature. ClinVar contains an entry for this variant (RCV000160461, RCV000119290 ). In summary, this is rare change that is not expected to impact CHEK2 protein. However the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 11, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 08, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2016 | The c.*7T>C alteration is located in the 3' untranslated region (3'UTR) of the CHEK2 gene. This alteration consists of a deletion of 1 nucleotides after the last coding exon of the CHEK2 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHEK2 c.*7T>C variant was not identified in the literature. The variant was identified in dbSNP (ID: rs121908710) as "With other allele", ClinVar (classified as benign by GeneDx; as likely being by Color; as uncertain significance by three submitters). The variant was identified in control databases in 40 of 260056 chromosomes at a frequency of 0.0002 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: European in 7 of 121970 chromosomes (freq: 0.00006), Ashkenazi Jewish in 33 of 9956 chromosomes (freq: 0.003), while the variant was not observed in the African, Other, Latino, East Asian, Finnish, and South Asian populations. 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
not provided Other:1
not provided, no classification provided | literature only | Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague | - | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at