22-28719480-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4
The NM_007194.4(CHEK2):c.598G>A(p.Val200Ile) 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. V200A) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
8
10
Clinical Significance
Conservation
PhyloP100: 4.18
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;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr22-28719479-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 973771.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.35198364).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.598G>A | p.Val200Ile | missense_variant | 5/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.598G>A | p.Val200Ile | missense_variant | 5/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 26
GnomAD4 exome
Cov.:
26
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 09, 2020 | This missense variant replaces valine with isoleucine at codon 200 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2022 | The p.V200I variant (also known as c.598G>A), located in coding exon 4 of the CHEK2 gene, results from a G to A substitution at nucleotide position 598. The valine at codon 200 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was identified in 1/488 patients with stages I to III breast cancer diagnosed over age 50 who were tested with a 25-gene panel test, and p.V200I was classified as a variant of uncertain significance (Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 2015 | This variant is denoted CHEK2 c.598G>A at the cDNA level, p.Val200Ile (V200I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Val200Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Val200Ile occurs at a position that is conserved in mammals and is located in the FHA domain (Roeb 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether CHEK2 Val200Ile is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2022 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 200 of the CHEK2 protein (p.Val200Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 182456). 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: "Benign"; 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.;T;T;.;T;.;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;L;.;L;.;L;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;.;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;.;T;T;T
Sift4G
Benign
T;T;T;T;T;.;T;T;T
Polyphen
B;D;B;B;P;B;D;D;.
Vest4
MutPred
Gain of methylation at K197 (P = 0.0935);Gain of methylation at K197 (P = 0.0935);Gain of methylation at K197 (P = 0.0935);Gain of methylation at K197 (P = 0.0935);.;Gain of methylation at K197 (P = 0.0935);.;Gain of methylation at K197 (P = 0.0935);.;
MVP
MPC
0.047
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