chr22-28734571-G-A

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.151C>T(p.Gln51*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q51Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.35

Publications

7 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 22-28734571-G-A is Pathogenic according to our data. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734571-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141231.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.151C>T	p.Gln51*	stop_gained	Exon 2 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.151C>T	p.Gln51*	stop_gained	Exon 2 of 15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251402

AF XY:

0.00000736

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000268

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:3

Aug 12, 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.Gln51*) 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 present in population databases (rs587781592, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with kidney cancer (PMID: 34308104). ClinVar contains an entry for this variant (Variation ID: 141231). For these reasons, this variant has been classified as Pathogenic. -

Jun 21, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 22, 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. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Jun 05, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Q51* pathogenic mutation (also known as c.151C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 151. This changes the amino acid from a glutamine to a stop codon within coding exon 1. 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. -

Sep 18, 2020

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant changes 1 nucleotide in exon 2 of the CHEK2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:1

Mar 22, 2023

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.95

PhyloP100

6.3

Vest4

0.82

GERP RS

5.4

PromoterAI

-0.012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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