22-28725099-A-G

Variant names:

• chr22-28725099-A-G
• rs17879961
• NM_007194.4:c.470T>C
• CHEK2 p.Ile157Thr

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PS3 PP5 BP4

The NM_001257387.3(CHEK2):​c.-308T>C variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00276 in 1,614,104 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars). ClinVar reports functional evidence for this variant: "SCV002318950: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID:33986034) - PS3_supporting."" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0040 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (29 hom.)
• Consequence: CHEK2 NM_001257387.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:35 U:11 O:4
• Conservation: PhyloP100: 6.65
• Publications: 584 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 4 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002318950: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 33986034) - PS3_supporting."; SCV004801675: Functional studies by Kilpivaara et al. (2004) demonstrated the variant protein was stable but dimerized with the normal CHEK2 protein when co-expressed in human cells, suggesting a dominant negative effect on the amount of normal CHEK2 protein in carriers of the variant. The p.Ile157Thr variant protein has also been shown to be defective in its ability to bind and phosphorylate Cdc25A and to bind p53 and BRCA1 (Falck et al. 2001a; Falck et al. 2001b; Li et al. 2002).; SCV000292120: Functional studies have shown that this variant does not significantly impact phosphorylation of a downstream target protein or CHEK2 autophosphorylation (PMID: 31050813, 34903604, 37449874) and results in a reduced binding of the CHEK2 protein to BRCA1, CDC25A and TP53 proteins in vitro and may have a dominant-negative effect on CHEK2 function (PMID: 11571648, 12049740, 15239132, 22419737).; SCV000821722: Experimental studies find that this missense change reduces the binding of the CHEK2 protein to Cdc25A, BRCA1 and p53 proteins in vitro and may have a dominant-negative effect in cells, although it does not have an effect on CHEK2 protein kinase activity (PMID: 11298456, 11571648, 15239132, 12049740, 22419737).; SCV000253984: Experimental studies find that this missense change reduces the binding of the CHEK2 protein to Cdc25A, BRCA1 and p53 proteins in vitro and may have a dominant-negative effect in cells, although it does not have an effect on CHEK2 protein kinase activity (PMID: 11298456, 11571648, 15239132, 12049740, 22419737).; SCV000839939: "In vitro and in vivo studies have shown that the mutant allele does not affect the kinase activity of the protein [PMID 11719428] but does affect the dimerization of the protein in a dominant negative manner, resulting in the lack of autophosphosphorylation [PMID 12805407]. The mutant protein also impaired the binding of CHEK2 to check point proteins including CDC25A in response to DNA damage [PMID 11298456]."; SCV000987254: "4 functional studies (PMID: 12049740, 15239132, 11298456, & 11571648) confirmed the likely pathogenic effect of this variant (PS3 Pathogenic Strong)."; SCV000149927: Published functional studies demonstrate a damaging effect with respect to autophosphorylation, binding of downstream targets, and DNA damage response, and may exhibit a dominant-negative effect, while studies assessing kinase activity have varied results (Falck 2001a, Falck 2001b, Lee 2001, Wu 2001, Li 2002, Schwarz 2003, Kilpivaara 2004, Roeb 2012, Delimitsou 2019, Kleiblova 2019, Boonen 2021); SCV001159433: "In vitro assays suggest the variant protein has wildtype kinase activity but fails to interact with normal binding partners (Falck 2001, Li 2002, Wu 2001)."; SCV002525957: Functional assays have reported that this variant affects the dimerization of the protein in a dominant negative manner resulting in a lack of autophosphorylation (PMID 12805407). In addition, functional assays have shown that the variant does not affect the kinase activity of the protein (PMID: 11719428), but it does impair the binding of CHEK2 to other proteins (PMID: 11298456, 12049740).; SCV004175292: Well-established functional studies show a deleterious effect of this variant (PS3).; SCV000806880: This variant negatively affects CHEK2 function through a possible dominant-negative mechanism (Kilpivaara et al. 2004. PubMed ID: 15239132; Roeb et al. 2012. PubMed ID: 22419737).; SCV002496051: These studies may not accurately represent biological function in humans and it is unclear how these findings may relate to cancer risk. However, these studies suggest a deleterious impact (Selected publications: Falck 2001 PMID:11298456; Falck 2001 PMID:11571648; Li 2002 PMID:12049740; Schwarz 2003 PMID:12805407; Roeb 2012 PMID:22419737).; SCV003919794: These studies may not accurately represent biological function in humans and it is unclear how these findings may relate to cancer risk. However, these studies suggest a deleterious impact (Selected publications: Falck 2001 PMID:11298456; Falck 2001 PMID:11571648; Li 2002 PMID:12049740; Schwarz 2003 PMID:12805407; Roeb 2012 PMID:22419737).; SCV006557383: Multiple experimental studies have reported evidence evaluating an impact on protein function, including retained kinase activity, decreased interaction with p53 and BRCA1 and impaired CHEK2 oligomerization with reduced autophosphorylation.
• PP5: Variant 22-28725099-A-G is Pathogenic according to our data. Variant chr22-28725099-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity|risk_factor. ClinVar VariationId is 5591.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009227961). . Strength limited to SUPPORTING due to the PP5.

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.470T>C	p.Ile157Thr	missense	Exon 4 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001257387.3		c.-308T>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 16	NP_001244316.1
	CHEK2	NM_001437942.1		c.-194T>C		5_prime_UTR_premature_start_codon_gain	Exon 3 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.470T>C	p.Ile157Thr	missense	Exon 4 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.599T>C	p.Ile200Thr	missense	Exon 5 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.444+144T>C		intron	N/A	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 615 AN: 152156 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0229

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00412 AC: 1036 AN: 251416 AF XY: 0.00395

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0247

Gnomad NFE exome AF: 0.00393

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00263 AC: 3843 AN: 1461830 Hom.: 29 Cov.: 32 AF XY: 0.00271 AC XY: 1972 AN XY: 727212

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.0263 AC: 1406 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00203 AC: 2252 AN: 1111984

Other (OTH) AF: 0.00237 AC: 143 AN: 60392

GnomAD4 genome AF: 0.00404 AC: 615 AN: 152274 Hom.: 8 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.000196 AC: 3 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0229 AC: 243 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00532 AC: 362 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00354 Hom.: 12

Bravo AF: 0.00136

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
9	2	-	Familial cancer of breast (12)
4	2	-	Hereditary cancer-predisposing syndrome (8)
4	2	-	not provided (7)
4	-	-	CHEK2-related cancer predisposition (7)
2	-	-	Breast and colorectal cancer, susceptibility to (2)
-	2	-	not specified (3)
1	-	-	Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition (1)
-	1	-	Breast and/or ovarian cancer (1)
1	-	-	CHEK2-related disorder (1)
1	-	-	Cystic fibrosis (1)
1	-	-	Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition (1)
1	-	-	Familial cancer of breast;C0585442:Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition (1)
-	1	-	Gastrointestinal carcinoma;C0206686:Adrenal cortex carcinoma (1)
-	1	-	Malignant tumor of breast (1)
1	-	-	Predisposition to cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	0.83	L
PhyloP100		6.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.54
Sift	Benign	0.062	T
Sift4G	Benign	0.35	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.51
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs17879961;

hg19: chr22-29121087;

COSMIC: COSV60417313;