rs764884641

Variant names:

• chr22-28709998-ATACT-A
• rs764884641
• NM_007194.4:c.846+4_846+7delAGTA

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PP3_Moderate PP5_Very_Strong BS2_Supporting

The NM_007194.4(CHEK2):​c.846+4_846+7delAGTA variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000287 in 1,428,834 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000254953: Studies have shown that this variant results in skipping of either exon 7 (in-frame) or exons 7-8 (out-of-frame) (PMID:30264118" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: CHEK2 NM_007194.4 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25 U:1
• Conservation: PhyloP100: 5.62
• Publications: 5 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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000254953: Studies have shown that this variant results in skipping of either exon 7 (in-frame) or exons 7-8 (out-of-frame) (PMID: 30264118; internal data). The resulting mRNA is expected to either preserve the integrity of the reading frame or undergo nonsense-mediated decay. This variant disrupts the serine/threonine kinase domain of the CHEK2 protein, which is essential for protein function (PMID: 30264118, 31843900, 29785007).; SCV000272956: RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).; SCV000910787: Functional RNA studies have shown that this variant produces two mutant transcripts (PMID: 31050813, 31843900, 37725924). One mutant transcript causes an out-of-frame skipping of exons 7 and 8, creating a frameshift and premature translation stop signal and is expected to result in an absent or non-functional protein product. The other mutant transcript causes an in-frame skipping of exon 7, creating a partial deletion of the kinase domain. A functional study has shown that a variant lacking exon 7 displays significantly decreased kinase activity (PMID: 31050813).; SCV000329279: Published functional studies demonstrate absent kinase activity (PMID: 31050813); SCV000888125: Experimental studies indicate this variant causes abnormal splicing and loss of CHEK2 protein kinase function (PMIDs: 37725924 (2024), 31843900 (2019), 31050813 (2019), 30264118 (2018)).; SCV003800241: Functional analyses demonstrate skipping of exon 7 or both exons 7 and 8, and also a significant decrease in kinase activity (Casadei 2019, Kleiblova 2019). PMID: 31843900. PMID: 31050813.; SCV002511770: The most pronounced variant effect results in a significantly diminished CHEK2 kinase activity in vitro in an experimental system that measured relative levels of CHK2-dependent KAP1-S473 phosphorylation in RPE1-CHEK2-KO cells. PMID: 25186627; SCV005045694: The other mutant transcript results in an in-frame skipping of exon 7, creating a partial deletion of the kinase domain and significantly decreased kinase activity (PMID: 31050813).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 22-28709998-ATACT-A is Pathogenic according to our data. Variant chr22-28709998-ATACT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 216652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 38 AD,Unknown gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.846+4_846+7delAGTA		splice_region intron	N/A	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.975+4_975+7delAGTA		splice_region intron	N/A	NP_001005735.1
	CHEK2	NM_001438293.1		c.939+4_939+7delAGTA		splice_region intron	N/A	NP_001425222.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.846+4_846+7delAGTA		splice_region intron	N/A	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.975+4_975+7delAGTA		splice_region intron	N/A	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.645+4_645+7delAGTA		splice_region intron	N/A	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000284 AC: 7 AN: 246676 AF XY: 0.0000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000541

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000298 AC: 38 AN: 1276596 Hom.: 0 AF XY: 0.0000310 AC XY: 20 AN XY: 644436

African (AFR) AF: 0.00 AC: 0 AN: 29598

American (AMR) AF: 0.0000453 AC: 2 AN: 44164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24764

East Asian (EAS) AF: 0.0000517 AC: 2 AN: 38696

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4172

European-Non Finnish (NFE) AF: 0.0000338 AC: 32 AN: 946460

Other (OTH) AF: 0.0000186 AC: 1 AN: 53860

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Familial cancer of breast (7)
6	-	-	not provided (6)
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
1	-	-	Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	Carcinoma of pancreas (1)
1	-	-	CHEK2-related cancer predisposition (1)
1	-	-	Endometrial carcinoma (1)
1	-	-	Familial cancer of breast;C5882668:CHEK2-related cancer predisposition (1)
1	-	-	Hereditary nonpolyposis colon cancer (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 8

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

Other links and lift over

dbSNP: rs764884641; hg19: chr22-29105986;