NM_007194.4:c.*18C>T

Variant names:

• chr22-28687879-G-A
• rs17884403
• NM_007194.4:c.*18C>T

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACGS-UK Somatic Oncogenicity v2025).

The NM_007194.4(CHEK2):c.*18C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The gene CHEK2 is a tumor suppressor gene (CancerMine: 11 TSG, 7 oncogene, 5 driver citations). The gene CHEK2 is a known oncogene (CancerMine: 11 TSG, 7 oncogene, 5 driver citations). The gene CHEK2 is a cancer driver gene (CancerMine: 11 TSG, 7 oncogene, 5 driver citations). The variant allele was found at a cumulative frequency of 0.000506 (AC=798) in the gnomAD database across 1,575,934 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.000614. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). The variant has been observed in cBioPortal in 3 samples across 2 studies and 1 cancer type; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (1 hom.)
• Consequence: CHEK2 NM_007194.4 3_prime_UTR
• Predictors: AlphaGenome AVI: 16: Uncertain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8
• Conservation: PhyloP100: -2.17
• Publications: 3 publications found

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, ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
No applied criteria Uncheck "Show applied only" above to review all 20 criteria.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_007194.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CHEK2 NM_007194.4	MANE Select	c.*18C>T	3_prime_UTR	Exon 15 of 15	Prot: NP_009125.1
	CHEK2 NM_001005735.3		c.*18C>T	3_prime_UTR	Exon 16 of 16	Prot: NP_001005735.1
	CHEK2 NM_001438293.1		c.*18C>T	3_prime_UTR	Exon 16 of 16	Prot: NP_001425222.1

CHEK2 NM_007194.4

MANE Select

HGVSc / HGVSpc.*18C>T

Exon rankExon 15 of 15

3_prime_UTR

Prot: NP_009125.1

CHEK2 NM_001005735.3

HGVSc / HGVSpc.*18C>T

Exon rankExon 16 of 16

3_prime_UTR

Prot: NP_001005735.1

CHEK2 NM_001438293.1

HGVSc / HGVSpc.*18C>T

Exon rankExon 16 of 16

3_prime_UTR

Prot: NP_001425222.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CHEK2 ENST00000404276.6	MANE Select	c.*18C>T	3_prime_UTR	Exon 15 of 15	Prot: ENSP00000385747
	CHEK2 ENST00000382580.7	TSL:1	c.*18C>T	3_prime_UTR	Exon 16 of 16	Prot: ENSP00000372023
	CHEK2 ENST00000416671.5	TSL:1	c.*1140C>T	3_prime_UTRNMD_transcript	Exon 16 of 16	Prot: ENSP00000402225

CHEK2 ENST00000404276.6

MANE Select

HGVSc / HGVSpc.*18C>T

Exon rankExon 15 of 15

3_prime_UTR

Prot: ENSP00000385747

CHEK2 ENST00000382580.7

TSL:1

HGVSc / HGVSpc.*18C>T

Exon rankExon 16 of 16

3_prime_UTR

Prot: ENSP00000372023

CHEK2 ENST00000416671.5

TSL:1

HGVSc / HGVSpc.*1140C>T

Exon rankExon 16 of 16

3_prime_UTRNMD_transcript

Prot: ENSP00000402225

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000338	AC:51	Hom:0	AN:150924	Cov:32
GnomAD2 exomes	AF: 0.000240	AC:56	Hom:	AN:233404	Cov:
GnomAD4 exome	AF: 0.000524	AC:747	Hom:1	AN:1424892	Cov:28
GnomAD4 genome	AF: 0.000338	AC:51	Hom:0	AN:151042	Cov:32
TOPMed (Bravo) Warning	AF: 0.000336	AC:89	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000448	AC:11	Hom:0	AN:24534	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
Denmark Genome	AF: 0.00667	AC:2	Hom:	AN:300	Cov:
UK10K	AF: 0.000926	AC:7	Hom:	AN:7562	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.000493	14	28420	0.000485	14	28844
SCHEMA(Schizophrenia)	0.000243	21	86268	0.000287	40	139280

Showing 2 cohortsAllele count / allele number. *AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	2	-	Familial cancer of breast (2)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	-	Breast and/or ovarian cancer (1)
-	1	-	CHEK2-related cancer predisposition (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.73
DANN	Benign	0.88
GPN-Star LLR	N/A	3.7
GPN-Star score	N/A	3.7
Mutation Taster	N/A	100/0	polymorphism
PhyloP100	Benign	-2.2
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs17884403;

hg19: chr22-29083867;

COSMIC: COSV60420597;

COSMIC: COSV60420597;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar