rs137853007

Variant names:

• chr22-28725254-G-A
• rs137853007
• NM_007194.4:c.433C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28725254-G-A
• chr22-28725254-G-C
• chr22-28725254-G-T

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_001257387.3(CHEK2):​c.-345C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,613,910 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000437721: Functional studies in cell lines and yeast cells demonstrated that p.Arg145Trp-CHEK2 protein has a reduced half-life compared with wild type CHEK2 and does not become activated in response to DNA damage (Lee et al. 2001" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: CHEK2 NM_001257387.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:34 O:1
• Conservation: PhyloP100: 3.37
• Publications: 84 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: SCV000437721: Functional studies in cell lines and yeast cells demonstrated that p.Arg145Trp-CHEK2 protein has a reduced half-life compared with wild type CHEK2 and does not become activated in response to DNA damage (Lee et al. 2001; Falck et al. 2001; Li et al. 2002; Sodha et al. 2006; Roeb et al. 2012).; SCV000185008: This variant is located in the FHA functional domain and multiple studies have demonstrated p.R145W abolishes normal CHK2 function, resulting in an unstable protein deficient in substrate binding/phosphorylation and overall DNA damage response (Lee SB et al. Cancer Res. 2001 Nov;61:8062-7; Falck J et al. Nature. 2001 Apr;410:842-7; Li J et al. Mol. Cell. 2002 May;9:1045-54). This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 May;40:631-648).; SCV000537624: Multiple functional studies have shown this variant to cause loss of CHEK2 kinase activity, DNA damage response, and cell cycle control function (PMID: 11053450, 11298456, 11390408, 11571648, 11719428, 22419737, 30851065, 34903604, 37449874). This reduced activity has been attributed to significantly reduced stability of the mutant protein (PMID: 12049740, 11719428, 16982735, 30851065, 34903604).; SCV005689644: PS3_SUP (PMID: 39146382); SCV000253711: Experimental studies have shown that this missense change affects CHEK2 function (PMID: 11298456, 11390408, 11571648, 11719428, 12049740, 15239132, 16982735).; SCV000839946: Functional studies showed that this mutant is defective of phosphorylation with significantly reduced kinase activity [PMID: 11053450, 11298456, 11390408, 11571648, 12049740, 22114986].; SCV000149925: Published functional studies demonstrate a damaging effect: decreased or absent kinase activity, impaired KAP1 phosphorylation and CHK2 auto-phosphorylation, deficient response to DNA damage, and inability to bind BRCA1 and TP53 (PMID: 37449874, 11571648, 11390408, 11053450, 12049740, 22114986, 22419737, 30851065, 34903604, 39146382); SCV001134168: Multiple functional studies have shown that this variant results in a CHEK2 protein with decreased stability and an inability to bind and phosphorylate other proteins (PMID: 37449874 (2023), 22419737 (2012), 16982735 (2006), 12049740 (2002), 11901158 (2002), 11719428 (2001), 11571648 (2001)).; SCV000698801: Several publications report experimental evidence evaluating an impact on protein function, demonstrating reduced protein stability and decreased CHEK2 function (e.g. Lee_2001, Li_2002, Roeb_2012, Delimitsou_2019, Boonen_2022).; SCV001553778: Several in vitro and in vivo functional studies have shown the variant have reduced catalytic activity and disrupted kinase activity (Falck 2001, Wu 2001, Desrichard 2011, Lee 2001).; SCV006324392: "We chose these criteria: PS3 (strong pathogenic): Stolarova (2023, PMID: 37449874) KAP1 & CHK2-assay, Boonen (2022, PMID: 34903604) & Delimitsou (2019, 30851065): damaging effect,"
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 22-28725254-G-A is Pathogenic according to our data. Variant chr22-28725254-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 5592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 7 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_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.433C>T	p.Arg145Trp	missense	Exon 3 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001257387.3		c.-345C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 16	NP_001244316.1
	CHEK2	NM_001437942.1		c.-231C>T		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.433C>T	p.Arg145Trp	missense	Exon 3 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.562C>T	p.Arg188Trp	missense	Exon 4 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.433C>T	p.Arg145Trp	missense	Exon 2 of 13	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152102 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: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251290 AF XY: 0.0000589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.0000523 AC XY: 38 AN XY: 727204

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

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000540 AC: 60 AN: 1111982

Other (OTH) AF: 0.0000662 AC: 4 AN: 60390

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15246

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

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

Alfa AF: 0.0000824 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Familial cancer of breast (9)
9	-	-	not provided (9)
6	-	-	Hereditary cancer-predisposing syndrome (6)
3	-	-	CHEK2-related cancer predisposition (3)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	Gastric cancer (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Li-Fraumeni syndrome (1)
1	-	-	Li-Fraumeni syndrome 1 (1)
1	-	-	Malignant tumor of breast (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.98
MPC		0.17
ClinPred		0.94	D
GERP RS		4.6
Varity_R		0.93
gMVP		0.76
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs137853007; hg19: chr22-29121242; COSMIC: COSV60416836; COSMIC: COSV60416836;