rs876658557

Variant names:

• chr22-28725319-T-C
• rs876658557
• NM_007194.4:c.368A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-28725319-T-C
• chr22-28725319-T-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_001257387.3(CHEK2):​c.-410A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000041 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CHEK2 NM_001257387.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 4.37
• 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: Likely_benign. The variant received -1 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD 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_001257387.3. 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.368A>G	p.Tyr123Cys	missense	Exon 3 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001257387.3		c.-410A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 16	NP_001244316.1
	CHEK2	NM_001437942.1		c.-296A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	NP_001424871.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.368A>G	p.Tyr123Cys	missense	Exon 3 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.497A>G	p.Tyr166Cys	missense	Exon 4 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.368A>G	p.Tyr123Cys	missense	Exon 2 of 13	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251314 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461778 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727196

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

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

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Familial cancer of breast (2)
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	Endometrial carcinoma (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.71
Sift	Benign	0.047	D
Sift4G	Benign	0.097	T
Polyphen		0.39	B
Vest4		0.89
MutPred		0.55		Loss of methylation at K119 (P = 0.0566)
MVP		0.96
MPC		0.10
ClinPred		0.90	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.66
Mutation Taster		=22/78	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: rs876658557; hg19: chr22-29121307;