rs587782849

Variant names:

• chr22-28724974-T-A
• rs587782849
• NM_007194.4:c.592+3A>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28724974-T-A
• chr22-28724974-T-C
• chr22-28724974-T-G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PS3 PP3 PP5_Very_Strong BS2_Supporting

The NM_007194.4(CHEK2):​c.592+3A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000187541: RNA analysis from an individual diagnosed with breast cancer who carried this variant identified two abnormally spliced transcripts predicted to result nonsense-mediated decay (Kraus C et al. Int. J. Cancer. 2017 Jan" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CHEK2 NM_007194.4 splice_region, intron
• Scores: Splicing: ADA: 0.9976
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28 U:2
• Conservation: PhyloP100: 3.10
• Publications: 15 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 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000187541: RNA analysis from an individual diagnosed with breast cancer who carried this variant identified two abnormally spliced transcripts predicted to result nonsense-mediated decay (Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102), and another RNA study demonstrated this alteration has a deleterious splicing impact (Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec). In addition, a mini-gene study reported that this variant produced no normally spliced transcripts (Sanoguera-Miralles L et al. Clin Chem. 2024 Jan;70(1):319-338).; SCV000537545: RNA studies with heterozygous carriers have shown that this variant causes aberrant splicing and causes out-of-frame skipping of exon 4, or exons 4 and 5 (PMID: 27616075, 31843900, 33925588).; SCV000289693: Studies have shown that this variant results in skipping of exon 4 and skipping of exon 4 and 5, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 27616075, 31843900, 33925588; internal data).; SCV004033931: PS3:Supporting; SCV001360505: Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5 prime splicing donor site, while two predict the variant weakens the 5 prime donor site. At least two publications report experimental evidence that this variant affects mRNA splicing, leading to the skipping of exon 4 and exon 4/5, both predicted to cause a frameshift (e.g. Kraus_2016, Casadei_2019).; SCV004118387: Functional analysis (RT-PCR) has demonstrated the formation of two different shortened CHEK2 transcripts, one lacking exon 4 and the other lacking exons 4-5 (Figure 1, Kraus et al. 2017. PubMed ID: 27616075).; SCV005373471: Studies have shown that this variant results in complex altered splicing including up regulation of naturally occurring isoforms and skipping of exon 4 (also known as exon 3) and skipping of exon 4 and 5, which introduce premature termination codons. This variant causes significant reduction of the normal transcript (PMID: 27616075, 31843900, 33925588).; SCV005416864: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
• PP5: Variant 22-28724974-T-A is Pathogenic according to our data. Variant chr22-28724974-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 142956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 22 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.592+3A>T		splice_region intron	N/A	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.721+3A>T		splice_region intron	N/A	NP_001005735.1
	CHEK2	NM_001438293.1		c.685+3A>T		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.592+3A>T		splice_region intron	N/A	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.721+3A>T		splice_region intron	N/A	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.445-51A>T		intron	N/A	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251318 AF XY: 0.0000221

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: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461750 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111910

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	not provided (9)
6	1	-	Familial cancer of breast (7)
4	-	-	Hereditary cancer-predisposing syndrome (4)
2	-	-	Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition (2)
2	-	-	CHEK2-related cancer predisposition (2)
-	1	-	Breast carcinoma (1)
1	-	-	CHEK2-related disorder (1)
1	-	-	Familial cancer of breast;C5882668:CHEK2-related cancer predisposition (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Malignant tumor of breast (1)
1	-	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.2
DANN	Benign	0.55
PhyloP100		3.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.63
Splicevardb		3.0
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.90		Position offset: 3

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

Other links and lift over

dbSNP: rs587782849; hg19: chr22-29120962;