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GeneBe

22-28687901-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007194.4(CHEK2):c.1628T>C(p.Leu543Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. L543V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CHEK2
NM_007194.4 missense

Scores

1
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.10
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08541253).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CHEK2NM_007194.4 linkuse as main transcriptc.1628T>C p.Leu543Ser missense_variant 15/15 ENST00000404276.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CHEK2ENST00000404276.6 linkuse as main transcriptc.1628T>C p.Leu543Ser missense_variant 15/151 NM_007194.4 P2O96017-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

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 submitterclinical testingInvitaeApr 23, 2023This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 543 of the CHEK2 protein (p.Leu543Ser). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1466164). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.097
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
16
DANN
Benign
0.95
DEOGEN2
Benign
0.18
T;.;T;.;T;.;T;.;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.00062
N
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.085
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
-0.14
N;.;N;.;N;.;N;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.48
T
PROVEAN
Benign
0.73
N;N;N;.;N;N;.;N;N
REVEL
Benign
0.054
Sift
Uncertain
0.0030
D;D;D;.;D;D;.;D;D
Sift4G
Pathogenic
0.0
D;D;D;.;D;D;.;D;D
Polyphen
0.0
B;B;B;.;B;B;B;B;B
Vest4
0.10
MutPred
0.37
Gain of catalytic residue at L543 (P = 0.0028);.;Gain of catalytic residue at L543 (P = 0.0028);.;Gain of catalytic residue at L543 (P = 0.0028);.;Gain of catalytic residue at L543 (P = 0.0028);.;.;
MVP
0.12
MPC
0.022
ClinPred
0.058
T
GERP RS
-0.62
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.035
gMVP
0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-29083889; COSMIC: COSV60422248; API