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22-28687890-A-G

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

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5O:1

Conservation

PhyloP100: -1.58
Variant links:
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: {Uncertain_significance=4, not_provided=1, Benign=1, Likely_benign=3}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CHEK2NM_007194.4 linkuse as main transcriptc.*7T>C 3_prime_UTR_variant 15/15 ENST00000404276.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CHEK2ENST00000404276.6 linkuse as main transcriptc.*7T>C 3_prime_UTR_variant 15/151 NM_007194.4 P2O96017-1

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000167
AC:
39
AN:
233610
Hom.:
1
AF XY:
0.000171
AC XY:
22
AN XY:
128306
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00324
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000552
Gnomad OTH exome
AF:
0.000168
GnomAD4 exome
AF:
0.000112
AC:
162
AN:
1441330
Hom.:
1
Cov.:
30
AF XY:
0.000111
AC XY:
80
AN XY:
717598
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00352
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000496
Gnomad4 OTH exome
AF:
0.000233
GnomAD4 genome
AF:
0.0000789
AC:
12
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000521
Hom.:
0
Bravo
AF:
0.0000907

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
Uncertain significance, criteria provided, single submitterclinical testingCounsylMar 18, 2016- -
Likely benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 16, 2015This 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
Benign, criteria provided, single submitterclinical testingGeneDxSep 08, 2014This 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 submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalFeb 06, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoOct 11, 2016- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 26, 2016The 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. -
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthSep 08, 2015- -
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria providedclinical testingDepartment 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 providedliterature onlyInstitute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.88
CADD
Benign
0.31
DANN
Benign
0.66
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908710; hg19: chr22-29083878; API