rs145754558

Variant summary

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

The NM_007194.4(CHEK2):​c.593-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,457,612 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0014 ( 21 hom. )

Consequence

CHEK2
NM_007194.4 intron

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.235
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 (BayesDel_noAF=-0.84).
BP6
Variant 22-28719499-G-A is Benign according to our data. Variant chr22-28719499-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28719499-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0014 (1825/1305342) while in subpopulation EAS AF= 0.0101 (386/38162). AF 95% confidence interval is 0.00928. There are 21 homozygotes in gnomad4_exome. There are 893 alleles in male gnomad4_exome subpopulation. Median coverage is 20. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHEK2NM_007194.4 linkc.593-14C>T intron_variant Intron 4 of 14 ENST00000404276.6 NP_009125.1 O96017-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHEK2ENST00000404276.6 linkc.593-14C>T intron_variant Intron 4 of 14 1 NM_007194.4 ENSP00000385747.1 O96017-1

Frequencies

GnomAD3 genomes
AF:
0.00237
AC:
360
AN:
152152
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00904
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.0202
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00126
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.00312
AC:
612
AN:
195858
Hom.:
8
AF XY:
0.00294
AC XY:
310
AN XY:
105400
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000347
Gnomad ASJ exome
AF:
0.00257
Gnomad EAS exome
AF:
0.00802
Gnomad SAS exome
AF:
0.000195
Gnomad FIN exome
AF:
0.0208
Gnomad NFE exome
AF:
0.000620
Gnomad OTH exome
AF:
0.00214
GnomAD4 exome
AF:
0.00140
AC:
1825
AN:
1305342
Hom.:
21
Cov.:
20
AF XY:
0.00137
AC XY:
893
AN XY:
653132
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000502
Gnomad4 ASJ exome
AF:
0.00228
Gnomad4 EAS exome
AF:
0.0101
Gnomad4 SAS exome
AF:
0.000252
Gnomad4 FIN exome
AF:
0.0194
Gnomad4 NFE exome
AF:
0.000294
Gnomad4 OTH exome
AF:
0.00150
GnomAD4 genome
AF:
0.00236
AC:
359
AN:
152270
Hom.:
3
Cov.:
32
AF XY:
0.00345
AC XY:
257
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00906
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.0202
Gnomad4 NFE
AF:
0.00126
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00255
Hom.:
0
Bravo
AF:
0.000570
Asia WGS
AF:
0.00839
AC:
29
AN:
3470

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 16, 2013
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 13, 2017
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

Familial cancer of breast Benign:3
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: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered 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]. -

Feb 09, 2016
Counsyl
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3
Jun 30, 2015
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely 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. -

Feb 03, 2025
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS1, BP4 c.593-14C>T is an intronic variant located close to a canonical splice site. The variant allele was found in 130/16644 alleles, with a filter allele frequency of 0.63% at 99% confidence in the gnomAD v2.1.1 database (East Asian)(BS1). The SpliceAI algorithm predicts no significant impact on splicing (BP4). To our knowledge, neither clinical data nor functional studies have been reported for this variant It has been identified in the following databases, ClinVar (10x benign, 3x likely benign) and LOVD (4x benign). Based on currently available information, the variant c.593-14C>T is classified as a likely benign variant according to ACMG guidelines. -

Aug 26, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

CHEK2-related cancer predisposition Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1
May 22, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The CHEK2 c.593-14C>T variant was not identified in the literature nor was it identified in the Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs145754558) as “With Likely benign allele”, ClinVar (as benign by GeneDx, Counsyl), Clinvitae (as benign by ClinVar), databases. The variant was identified in control databases in 752 of 221734 (8 homozygous) chromosomes at a frequency of 0.003 in the following populations: other in 22 of 5482 chromosomes (freq. 0.004), Latino in 1 of 28996 chromosomes (freq. 0.000034), European in 114 of 93630 (1 homozygous) chromosomes (freq. 0.0012), Ashkenazi Jewish in 22 of 9042 chromosomes (freq. 0.0024), East Asian in 128 of 16184 (1 homozygous) chromosomes (freq. 0.008), Finnish in 460 of 22300 (6 homozygous) chromosomes (freq. 0.02),and South Asian in 5 of 25738 chromosomes (freq. 0.0002), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:1
Apr 19, 2022
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
CADD
Benign
2.3
DANN
Benign
0.52

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: rs145754558; hg19: chr22-29115487; API