rs374938148

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_007194.4(CHEK2):c.-4C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000955 in 1,611,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15B:2

Conservation

PhyloP100: -0.734

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.-4C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 15	ENST00000404276.6	NP_009125.1	O96017-1
CHEK2	NM_007194.4 link	c.-4C>T	splice_region_variant	Exon 2 of 15	ENST00000404276.6	NP_009125.1	O96017-1
CHEK2	NM_007194.4 link	c.-4C>T	5_prime_UTR_variant	Exon 2 of 15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHEK2	ENST00000404276.6 link	c.-4C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 15	1	NM_007194.4	ENSP00000385747.1	O96017-1
CHEK2	ENST00000404276.6 link	c.-4C>T	splice_region_variant	Exon 2 of 15	1	NM_007194.4	ENSP00000385747.1	O96017-1
CHEK2	ENST00000404276.6 link	c.-4C>T	5_prime_UTR_variant	Exon 2 of 15	1	NM_007194.4	ENSP00000385747.1	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.000139

AC:

AN:

150708

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000978

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000665

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000483

GnomAD3 exomes

AF:

0.0000573

AC:

AN:

244274

Hom.:

AF XY:

0.0000528

AC XY:

AN XY:

132492

show subpopulations

Gnomad AFR exome

AF:

0.0000628

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000111

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000910

AC:

133

AN:

1461068

Hom.:

Cov.:

AF XY:

0.0000881

AC XY:

AN XY:

726800

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000114

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000139

AC:

AN:

150708

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

AN XY:

73390

show subpopulations

Gnomad4 AFR

AF:

0.0000978

Gnomad4 AMR

AF:

0.0000665

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000483

Alfa

AF:

0.0000967

Hom.:

Bravo

AF:

0.000132

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Dec 23, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with breast, ovarian, or pancreatic cancer (PMID: 17145815, 28779002, 29522266, 31784482, 34326862, 34371384, 35264596, 35534704, 35886069); Not observed at significant frequency in large population cohorts (gnomAD); Nucleotide is not conserved across species and the substitution has no predicted effect on splicing; Describes a nucleotide substitution 4 base pairs upstream of the ATG translational start site of the CHEK2 gene, occurring in the consensus Kozak sequence, the nucleotides just upstream of the ATG start codon, which play a major role in the initiation of translation; This variant is associated with the following publications: (PMID: 31784482, 17145815, 28779002, 21681852, 29522266, 35886069, 34371384, 35264596, 35896598, 34326862, 35534704) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 29, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHEK2 c.-4C>T variant has been reported in the published literature in individuals with breast cancer (PMIDs: 28779002 (2017), 35886069 (2022), 35534704 (2022), and 35264596 (2022)), in an individual with unspecified breast/ovarian or pancreatic cancer (PMID: 34371384 (2021)), in chronic myeloid leukemia with a causative variant in another gene (PMID: 35896598 (2022)), and an individual with ovarian cancer whose tumor showed loss of heterozygosity and low protein expression by immunohistochemistry (PMID: 17145815 (2006)). The frequency of this variant in the general population, 0.00011 (12/107708 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect CHEK2 mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cancer of breast

Uncertain:4

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the CHEK2 gene. It does not change the encoded amino acid sequence of the CHEK2 protein. This variant is present in population databases (rs374938148, gnomAD 0.01%). This variant has been observed in individual(s) with CHEK2-related conditions (PMID: 4326862, 17145815, 28779002, 35264596, 35886069). ClinVar contains an entry for this variant (Variation ID: 128039). 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. -

Sep 20, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Hereditary cancer-predisposing syndrome

Uncertain:3Benign:1

Aug 11, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 26, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2025

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The splice region variant NM_001005735.2(CHEK2):c.-4C>T has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.-4C>T variant is not predicted to disrupt the existing acceptor splice site 3bp upstream by any splice site algorithm. The c.-4C>T variant is not predicted to introduce a novel splice site by any splice site algorithm. For these reasons, this variant has been classified as Uncertain Significance -

Apr 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-4C>T variant is located in the 5' untranslated region (5’ UTR) of the CHEK2 gene. This variant results from a C to T substitution 4 bases upstream from the first translated codon. This variant has been reported in a woman with ovarian cancer whose tumor showed loss of heterozygosity at the CHEK2 locus (Williams LH et al. Clin. Cancer Res. 2006 Dec;12:6967-72). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This nucleotide position is not well conserved in available vertebrate species. This alteration is predicted to slightly decrease the efficiency of the native splice acceptor site by the BDGP and ESEfinder in silico models. RNA studies have demonstrated this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CHEK2 c.-4C>T is located in the untranslated mRNA region upstream of the initiation codon. This variant lies within the Kozak sequence, a region that plays a role in the initiation of translation. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. The variant allele was found at a frequency of 5.7e-05 in 244790 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Li-Fraumeni Syndrome phenotype (2.8e-05), strongly suggesting that the variant is benign. c.-4C>T has been reported in the literature in individuals affected with breast cancer (e.g. Decker_2017, Paduano_2022, Guindalini_2022) or unspecified breast/ovarian or pancreatic cancer (e.g. Bono_2021), both without evidence of causality, in chronic myeloid leukemia with other reportedly causative variants (e.g. Kazemi-Sefat_2022), and in ovarian cancer with tumor loss of heterozygosity and faint protein expression by IHC, suggesting a potential role of the variant in tumorigenesis (e.g.Williams_2006). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.1517T>C, p.V506A), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 34371384, 28779002, 35264596, 35896598, 35886069, 17145815, 21681852). ClinVar contains an entry for this variant (Variation ID: 128039). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Familial ovarian cancer

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHEK2 c.-4C>T variant was identified in 1 of 238 proband chromosomes (frequency: 0.004) from individuals or families with ovarian cancer and was not identified in 516 control chromosomes from healthy individuals (Williams 2006). The variant was also identified in dbSNP (ID: rs374938148) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Counsyl, and Integrated Genetics/Laboratory Corporation of America). The variant was not identified in Cosmic, or Zhejiang University databases. The variant was identified in control databases in 15 of 238966 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 14970 chromosomes (freq: 0.00007), European in 13 of 105550 chromosomes (freq: 0.0001), and South Asian in 1 of 30676 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The c.-4C>T variant is located in the Kozak consensus sequence, and although typically the -4 position is a cytosine it is known to be variable. One study showed this variant resulted in weak CHEK2 immunoreactivity in an ovarian tumour sample (Williams 2006). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Mar 11, 2025

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

CHEK2-related disorder

Benign:1

Jul 09, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

6.9

DANN

Benign

0.84

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over