22-28695868-AG-A

Variant names:

• chr22-28695868-AG-A
• rs555607708
• NM_007194.4:c.1100delC

Germline classificationCancer classification (beta)

Variant summary

Our verdict is

Pathogenic

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 11 ACMG points: 11P and 0B. O1_ModerateO2_Very_StrongO4_Supporting

The NM_007194.4(CHEK2):c.1100delC (p.Thr367MetfsTer15) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). 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 0.00172 (AC=262) in the gnomAD database across 152,324 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00188. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.67). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000915968: Studies by Lee et al. (2001) found a lack of kinase activity and evidence of loss of heterozygosity in a tumor sample from a patient carrying the germline p.Thr367MetfsTer15 variant." and additional evidence is available in ClinVar. The variant has been observed in cBioPortal in 13 samples across 8 studies and 8 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHEK2 NM_007194.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:95 U:1 O:2
• Conservation: PhyloP100: 8.67
• Publications: 862 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: ClinGen, Ambry Genetics
• 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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• O1: TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (2.0 pts): ClinVar germline P/LP in TSG (★★)
• O2: Frameshift/stop-gained, NMD predicted, LoF oncogenic mechanism — O2 very strong (+8); Use caution in the presence of multiple transcripts; Gene confirmed as TSG in CancerMine (TSG: 11 citations, oncogene: 7 citations, driver: 5 citations).; Frameshift/stop-gained. NMD predicted: true. LoF mechanism: true. Downstream pathogenic count: 0.
• O4: Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=13 | studies=8 | cancer types=8 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	NM_007194.4	MANE Select	c.1100delC	p.Thr367MetfsTer15	frameshift	Exon 11 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.1229delC	p.Thr410MetfsTer15	frameshift	Exon 12 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.1193delC	p.Thr398MetfsTer15	frameshift	Exon 12 of 16	NP_001425222.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.1100delC	p.Thr367MetfsTer15	frameshift	Exon 11 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.1229delC	p.Thr410MetfsTer15	frameshift	Exon 12 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.899delC	p.Thr300MetfsTer15	frameshift	Exon 9 of 13	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00904

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00204 AC: 509 AN: 248982 AF XY: 0.00203

Gnomad AFR exome AF: 0.000395

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00873

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00165

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00220 AC: 3205 AN: 1459022 Hom.: 5 Cov.: 30 AF XY: 0.00213 AC XY: 1548 AN XY: 726030

African (AFR) AF: 0.000150 AC: 5 AN: 33422

American (AMR) AF: 0.0000224 AC: 1 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86200

European-Finnish (FIN) AF: 0.00848 AC: 453 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00236 AC: 2620 AN: 1109400

Other (OTH) AF: 0.00148 AC: 89 AN: 60306

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74480

African (AFR) AF: 0.000265 AC: 11 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00904 AC: 96 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00216 AC: 147 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000595 Hom.: 1

Bravo AF: 0.00100

EpiCase AF: 0.00185

EpiControl AF: 0.00130

Local populations

Turkish Variome AF: 0.000206 AC: 1 AN: 4462 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
21	-	-	not provided (22)
14	-	-	CHEK2-related cancer predisposition (15)
14	-	-	Familial cancer of breast (14)
13	-	-	Hereditary cancer-predisposing syndrome (13)
3	-	-	Colorectal cancer (3)
3	-	-	Inherited breast cancer and ovarian cancer (3)
3	-	-	Inherited prostate cancer (3)
2	-	-	Breast and/or ovarian cancer (2)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
-	1	-	Astrocytoma (1)
1	-	-	Bone osteosarcoma (1)
1	-	-	Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition (1)
1	-	-	Breast and colorectal cancer, susceptibility to (1)
1	-	-	Breast cancer, susceptibility to (1)
1	-	-	Breast carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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.

Other links and lift over

dbSNP: rs555607708;

hg19: chr22-29091856;

COSMIC: COSV60419771;

COSMIC: COSV60419771;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar