22-28694066-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_007194.4(CHEK2):​c.1427C>A​(p.Thr476Lys) 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 pathogenic 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. T476M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CHEK2
NM_007194.4 missense

Scores

4
10
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 3.15
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 Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr22-28694066-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHEK2NM_007194.4 linkc.1427C>A p.Thr476Lys missense_variant Exon 13 of 15 ENST00000404276.6 NP_009125.1 O96017-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHEK2ENST00000404276.6 linkc.1427C>A p.Thr476Lys missense_variant Exon 13 of 15 1 NM_007194.4 ENSP00000385747.1 O96017-1

Frequencies

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

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:4
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 20, 2023This missense variant replaces threonine with lysine at codon 476 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). Functional studies demonstrated this variant had intermediate activity in a yeast DNA damage response assay (PMID: 22419737) but similar kinase activity to wild-type (PMID: 16835864). This variant has been observed in a prostate tumor sample (PMID: 16835864) and an individual referred for genetic testing (PMID: 31159747). 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 submitterclinical testingGeneKor MSAAug 01, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 14, 2023The p.T476K variant (also known as c.1427C>A), located in coding exon 12 of the CHEK2 gene, results from a C to A substitution at nucleotide position 1427. The threonine at codon 476 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). A yeast based complementation assay demonstrated that this alteration produced intermediate growth compared to wild-type and negative controls (Roeb, Higgens, and King. Hum. Mol. Genet. 2012 Jun; 21(12):2738-44). In addition, functional assays of CHEK2 kinase activity demonstrated that this alteration results in partially reduced activity (Wu X et al. Hum. Mutat. 2006 Aug; 27(8):742-7). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4May 19, 2021- -
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 12, 2024This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 476 of the CHEK2 protein (p.Thr476Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with prostate cancer (PMID: 16835864). ClinVar contains an entry for this variant (Variation ID: 486833). 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 tolerated. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 16835864, 22419737). 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. -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 16, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.31
T;.;T;.;T;.;T;.;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.88
.;D;.;D;.;D;D;D;.
M_CAP
Benign
0.016
T
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.47
T
MutationAssessor
Uncertain
2.2
M;.;M;.;M;.;M;.;.
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-4.5
D;D;D;.;D;D;.;D;D
REVEL
Uncertain
0.45
Sift
Uncertain
0.0020
D;D;D;.;D;D;.;D;D
Sift4G
Uncertain
0.0040
D;D;D;.;D;D;.;D;D
Polyphen
1.0
D;D;D;.;D;D;D;D;D
Vest4
0.56
MutPred
0.87
Gain of ubiquitination at T476 (P = 0.0247);.;Gain of ubiquitination at T476 (P = 0.0247);.;Gain of ubiquitination at T476 (P = 0.0247);.;Gain of ubiquitination at T476 (P = 0.0247);.;.;
MVP
0.76
MPC
0.035
ClinPred
0.98
D
GERP RS
4.4
Varity_R
0.86
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs142763740; hg19: chr22-29090054; API