22-28687879-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_007194.4(CHEK2):c.*18C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000351 (AC=5) in the gnomAD database across 1,424,970 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000086. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CHEK2 NM_007194.4 3_prime_UTR
• Predictors: AlphaGenome AVI: 19: Uncertain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.17
• Publications: 0 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000086 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00276) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

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>G	3_prime_UTR	Exon 15 of 15	Prot: NP_009125.1
	CHEK2 NM_001005735.3		c.*18C>G	3_prime_UTR	Exon 16 of 16	Prot: NP_001005735.1
	CHEK2 NM_001438293.1		c.*18C>G	3_prime_UTR	Exon 16 of 16	Prot: NP_001425222.1

CHEK2 NM_007194.4

MANE Select

HGVSc / HGVSpc.*18C>G

Exon rankExon 15 of 15

3_prime_UTR

Prot: NP_009125.1

CHEK2 NM_001005735.3

HGVSc / HGVSpc.*18C>G

Exon rankExon 16 of 16

3_prime_UTR

Prot: NP_001005735.1

CHEK2 NM_001438293.1

HGVSc / HGVSpc.*18C>G

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>G	3_prime_UTR	Exon 15 of 15	Prot: ENSP00000385747
	CHEK2 ENST00000382580.7	TSL:1	c.*18C>G	3_prime_UTR	Exon 16 of 16	Prot: ENSP00000372023
	CHEK2 ENST00000416671.5	TSL:1	c.*1140C>G	3_prime_UTRNMD_transcript	Exon 16 of 16	Prot: ENSP00000402225

CHEK2 ENST00000404276.6

MANE Select

HGVSc / HGVSpc.*18C>G

Exon rankExon 15 of 15

3_prime_UTR

Prot: ENSP00000385747

CHEK2 ENST00000382580.7

TSL:1

HGVSc / HGVSpc.*18C>G

Exon rankExon 16 of 16

3_prime_UTR

Prot: ENSP00000372023

CHEK2 ENST00000416671.5

TSL:1

HGVSc / HGVSpc.*1140C>G

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 0.00000351	AC:5	Hom:0	AN:1424970	Cov:28
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	19
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.25
DANN	Benign	0.75
GPN-Star LLR	N/A	0.83
GPN-Star score	N/A	-0.83
PhyloP100	Benign	-2.2
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.050
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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar