22-28719470-T-C

Variant names:

• chr22-28719470-T-C
• rs587782813
• NM_007194.4:c.608A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_007194.4(CHEK2):​c.608A>G​(p.Asp203Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000252 in 1,589,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D203E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 5.97
• Publications: 7 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 46 uncertain in NM_007194.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

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.608A>G	p.Asp203Gly	missense	Exon 5 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.737A>G	p.Asp246Gly	missense	Exon 6 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.701A>G	p.Asp234Gly	missense	Exon 6 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.608A>G	p.Asp203Gly	missense	Exon 5 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.737A>G	p.Asp246Gly	missense	Exon 6 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000403642.5	TSL:1	c.335A>G	p.Asp112Gly	missense	Exon 2 of 12	ENSP00000384919.1	O96017-4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.00

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437290 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 714034

African (AFR) AF: 0.00 AC: 0 AN: 33112

American (AMR) AF: 0.00 AC: 0 AN: 42760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25426

East Asian (EAS) AF: 0.00 AC: 0 AN: 39362

South Asian (SAS) AF: 0.00 AC: 0 AN: 83662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096088

Other (OTH) AF: 0.00 AC: 0 AN: 59342

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74308

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.0000656 AC: 1 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Familial cancer of breast (3)
-	3	-	Hereditary cancer-predisposing syndrome (3)
-	2	-	not provided (2)
-	1	-	CHEK2-related cancer predisposition (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Benign	0.80
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.016	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.56		Loss of stability (P = 0.0035)
MVP		0.97
MPC		0.17
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.79
gMVP		0.73
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587782813; hg19: chr22-29115458;