rs786203977
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2
The NM_007194.4(CHEK2):c.3G>T(p.Met1?) variant causes a start lost 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 (★).
Frequency
Genomes: not found (cov: 31)
Consequence
CHEK2
NM_007194.4 start_lost
NM_007194.4 start_lost
Scores
5
7
3
Clinical Significance
Conservation
PhyloP100: 4.41
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 Pathogenic. Variant got 12 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_007194.4 (CHEK2) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 1794563
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.3G>T | p.Met1? | start_lost | 2/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.3G>T | p.Met1? | start_lost | 2/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 28, 2017 | In summary, this variant has uncertain impact on CHEK2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with a CHEK2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the CHEK2 mRNA. Because the nearest downstream methionine that can be used to initiate translation of CHEK2 lies at codon 46, it is not known if this variant results in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.;T;T;.;T;.;.;.;.;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
PROVEAN
Benign
N;N;N;N;N;.;N;N;N;N;N;.;N
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D;D;.;D;D;D;D;D;.;D
Sift4G
Pathogenic
D;D;D;D;D;.;D;D;D;D;D;.;.
Polyphen
B;B;B;B;P;B;B;B;.;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);
MVP
ClinPred
D
GERP RS
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