rs1060502719
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_007194.4(CHEK2):c.749T>C(p.Ile250Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I250I) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
3
7
8
Clinical Significance
Conservation
PhyloP100: 5.68
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 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.806
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.749T>C | p.Ile250Thr | missense_variant | 6/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.749T>C | p.Ile250Thr | missense_variant | 6/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251362Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135870
GnomAD3 exomes
AF:
AC:
1
AN:
251362
Hom.:
AF XY:
AC XY:
0
AN XY:
135870
Gnomad AFR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad SAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 17, 2022 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 09, 2022 | The p.I250T variant (also known as c.749T>C), located in coding exon 5 of the CHEK2 gene, results from a T to C substitution at nucleotide position 749. The isoleucine at codon 250 is replaced by threonine, an amino acid with similar properties. 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. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 250 of the CHEK2 protein (p.Ile250Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 410060). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.;T;.;T;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L;.;L;.;L;.;L;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;.;D;D;.;D;D;D;.;D;D
REVEL
Benign
Sift
Benign
T;T;T;.;T;T;.;T;T;D;.;T;T
Sift4G
Benign
T;T;T;.;T;T;.;T;T;T;.;.;T
Polyphen
P;P;P;.;P;P;P;P;P;.;.;.;.
Vest4
MutPred
Gain of disorder (P = 0.0438);Gain of disorder (P = 0.0438);Gain of disorder (P = 0.0438);.;Gain of disorder (P = 0.0438);.;Gain of disorder (P = 0.0438);.;Gain of disorder (P = 0.0438);.;.;.;.;
MVP
MPC
0.16
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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at