rs17886163

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007194.4(CHEK2):ā€‹c.1343T>Gā€‹(p.Ile448Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000961 in 1,612,248 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0051 ( 5 hom., cov: 32)
Exomes š‘“: 0.00053 ( 6 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

1
4
13

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: 7.38
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.008066297).
BP6
Variant 22-28695159-A-C is Benign according to our data. Variant chr22-28695159-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 133892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695159-A-C is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0051 (776/152298) while in subpopulation AFR AF= 0.0178 (741/41560). AF 95% confidence interval is 0.0168. There are 5 homozygotes in gnomad4. There are 347 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHEK2NM_007194.4 linkc.1343T>G p.Ile448Ser missense_variant Exon 12 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.1343T>G p.Ile448Ser missense_variant Exon 12 of 15 1 NM_007194.4 ENSP00000385747.1 O96017-1

Frequencies

GnomAD3 genomes
AF:
0.00510
AC:
776
AN:
152180
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0179
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00144
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00430
GnomAD3 exomes
AF:
0.00140
AC:
351
AN:
251084
Hom.:
2
AF XY:
0.000988
AC XY:
134
AN XY:
135686
show subpopulations
Gnomad AFR exome
AF:
0.0202
Gnomad AMR exome
AF:
0.000463
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.000530
AC:
774
AN:
1459950
Hom.:
6
Cov.:
30
AF XY:
0.000439
AC XY:
319
AN XY:
726396
show subpopulations
Gnomad4 AFR exome
AF:
0.0203
Gnomad4 AMR exome
AF:
0.000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.000845
GnomAD4 genome
AF:
0.00510
AC:
776
AN:
152298
Hom.:
5
Cov.:
32
AF XY:
0.00466
AC XY:
347
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.0178
Gnomad4 AMR
AF:
0.00144
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00426
Alfa
AF:
0.00134
Hom.:
0
Bravo
AF:
0.00571
ESP6500AA
AF:
0.0197
AC:
87
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00187
AC:
227

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:18Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4Other:1
Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Apr 06, 2018
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 03, 2021
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 31, 2017
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:4
Jul 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CHEK2: BP4, BS1, BS2 -

Nov 30, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24728327, 27595995, 21244692, 26976419, 30851065) -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Sep 01, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial cancer of breast Benign:4
Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 09, 2023
Myriad Genetics, Inc.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Mar 28, 2016
Counsyl
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4
Nov 22, 2014
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 24, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jan 12, 2018
True Health Diagnostics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 28, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Li-Fraumeni syndrome 2 Benign:1
Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1
May 25, 2022
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.22
CADD
Pathogenic
26
DANN
Benign
0.96
DEOGEN2
Benign
0.077
T;.;T;.;T;.;T;.;.
Eigen
Benign
0.028
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.87
.;D;.;T;.;T;T;T;.
MetaRNN
Benign
0.0081
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
0.69
N;.;N;.;N;.;N;.;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.60
N;N;N;.;N;N;.;N;N
REVEL
Benign
0.14
Sift
Benign
0.71
T;T;T;.;T;T;.;T;T
Sift4G
Benign
0.75
T;T;T;.;T;T;.;T;T
Polyphen
0.12
B;P;B;.;B;B;B;P;P
Vest4
0.57
MVP
0.68
MPC
0.045
ClinPred
0.040
T
GERP RS
5.9
Varity_R
0.49
gMVP
0.82

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

LitVar

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

Other links and lift over

dbSNP: rs17886163; hg19: chr22-29091147; COSMIC: COSV99049072; COSMIC: COSV99049072; API