NM_007194.4:c.817G>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_007194.4(CHEK2):c.817G>T(p.Glu273*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CHEK2
NM_007194.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.76

Publications

14 publications found

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]

CHEK2 Gene-Disease associations (from GenCC):

CHEK2-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
Li-Fraumeni syndrome 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
acute myeloid leukemia
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-28710035-C-A is Pathogenic according to our data. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710035-C-A is described in CliVar as Pathogenic. Clinvar id is 2584308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.817G>T	p.Glu273*	stop_gained	Exon 7 of 15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 link	c.817G>T	p.Glu273*	stop_gained	Exon 7 of 15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250122

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1404496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701746

African (AFR)

AF:

0.00

AC:

AN:

32212

American (AMR)

AF:

0.00

AC:

AN:

44464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25636

East Asian (EAS)

AF:

0.00

AC:

AN:

39330

South Asian (SAS)

AF:

0.00

AC:

AN:

84894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4482

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1062056

Other (OTH)

AF:

0.00

AC:

AN:

58192

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:2

Jun 27, 2023

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Apr 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Glu273*) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2584308). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Nov 18, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E273* pathogenic mutation (also known as c.817G>T), located in coding exon 6 of the CHEK2 gene, results from a G to T substitution at nucleotide position 817. This changes the amino acid from a glutamic acid to a stop codon within coding exon 6. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Feb 06, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CHEK2 c.817G>T (p.Glu273X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250122 control chromosomes (gnomAD). c.817G>T has been reported in the literature in individuals affected with hereditary breast and ovarian cancer syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with hereditary breast and ovarian cancer syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 2584308). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.81

PhyloP100

4.8

Vest4

0.94

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=0/200

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over