rs1555932427
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_007194.4(CHEK2):c.163T>G(p.Ser55Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S55F) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 31)
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
11
7
Clinical Significance
Conservation
PhyloP100: 5.92
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.30048648).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.163T>G | p.Ser55Ala | missense_variant | 2/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.163T>G | p.Ser55Ala | missense_variant | 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:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 04, 2022 | This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 55 of the CHEK2 protein (p.Ser55Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25503501). ClinVar contains an entry for this variant (Variation ID: 460816). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 28, 2022 | The p.S55A variant (also known as c.163T>G), located in coding exon 1 of the CHEK2 gene, results from a T to G substitution at nucleotide position 163. The serine at codon 55 is replaced by alanine, an amino acid with similar properties. This alteration was identified in 1/278 individuals from a cohort BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet Med, 2015 Aug;17:630-8). This amino acid position is well 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T;T;.;T;.;.;.;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;M;M;M;M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;.;N;N;N;N;N;.;.
REVEL
Benign
Sift
Uncertain
D;D;D;D;D;.;D;D;D;D;D;.;.
Sift4G
Benign
T;T;T;T;T;.;D;T;T;D;T;.;.
Polyphen
P;D;P;P;P;P;P;D;.;.;.;.;.
Vest4
MutPred
Loss of phosphorylation at S55 (P = 0.003);Loss of phosphorylation at S55 (P = 0.003);Loss of phosphorylation at S55 (P = 0.003);Loss of phosphorylation at S55 (P = 0.003);Loss of phosphorylation at S55 (P = 0.003);Loss of phosphorylation at S55 (P = 0.003);Loss of phosphorylation at S55 (P = 0.003);Loss of phosphorylation at S55 (P = 0.003);Loss of phosphorylation at S55 (P = 0.003);Loss of phosphorylation at S55 (P = 0.003);Loss of phosphorylation at S55 (P = 0.003);Loss of phosphorylation at S55 (P = 0.003);Loss of phosphorylation at S55 (P = 0.003);
MVP
MPC
0.13
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