rs142763740

Variant names:

• chr22-28694066-G-A
• rs142763740
• NM_007194.4:c.1427C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28694066-G-A
• chr22-28694066-G-C
• chr22-28694066-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 7P and 2B. PS3 PM1 PP5 BP4 BS2_Supporting

The NM_007194.4(CHEK2):​c.1427C>T​(p.Thr476Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,595,894 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000821724: "algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein, a prediction supported also by experimental studies." PMID:22114986, PMID:22419737" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T476K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (1 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:24 U:30 B:1 O:2
• Conservation: PhyloP100: 3.15
• Publications: 81 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.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000821724: "algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein, a prediction supported also by experimental studies." PMID:22114986, PMID:22419737; SCV003799997: "In vitro kinase assays and in vivo DNA damage response assays with the variant protein showed a loss of kinase activity and impaired function (Delimitsou 2019, Desrichard 2011, Kleiblova 2019, Roeb 2012)."; SCV000437714: The variant was absent from a total of 1,622 controls, but is reported at a frequency of 0.00068 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Desrichard et al. (2011) developed an in vitro kinase activity assay to assess the activity of missense variants in CHEK2. In this assay the p.Thr476Met variant demonstrated no kinase activity and was similar to a known non-functional kinase variant of CHEK2. In addition, Roeb et al. (2012) developed a yeast-based in-vivo functional assay to assess the effect of CHEK2 variants on the repair of DNA damage. Cells with wild-type CHEK2 repaired the DNA damage while cells with a known non-functional variant of CHEK2 did not. The p.Thr476Met variant was shown to have loss of function by this DNA damage response assay.; SCV000914986: Desrichard et al. (2011) developed an in vitro kinase activity assay to assess the activity of missense variants in CHEK2. In this assay the p.Thr476Met variant demonstrated no kinase activity and was similar to a known non-functional kinase variant of CHEK2. PMID:21965316 Roeb et al. (2012) developed a yeast-based in-vivo functional assay to assess the effect of CHEK2 variants on the repair of DNA damage. Cells with wild type CHEK2 repaired the DNA damage while cells with a known non-functional variant of CHEK2 did not. The p.Thr476Met variant was shown to have loss of function by this DNA damage response assay. PMID:22843597; SCV000806869: "In vitro and in vivo experimental studies suggest this variant results in reduced or absent kinase activity and DNA damage response (Desrichard et al. 2011. PubMed ID: 22114986; Table 1, Roeb et al. 2012. PubMed ID: 22419737; Figure 1, Kleiblova et al. 2019. PubMed ID: 31050813). An additional functional study using protein expression in yeast found that his variant results in semi-functional kinase activity (Delimitsou et al. 2019. PubMed ID: 30851065)."
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 47 uncertain in NM_007194.4
• PP5: Variant 22-28694066-G-A is Pathogenic according to our data. Variant chr22-28694066-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128060.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34246725). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 47 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.1427C>T	p.Thr476Met	missense	Exon 13 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.1556C>T	p.Thr519Met	missense	Exon 14 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.1520C>T	p.Thr507Met	missense	Exon 14 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.1427C>T	p.Thr476Met	missense	Exon 13 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.1556C>T	p.Thr519Met	missense	Exon 14 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.1226C>T	p.Thr409Met	missense	Exon 11 of 13	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000529

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000329 AC: 77 AN: 233796 AF XY: 0.000335

Gnomad AFR exome AF: 0.000204

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000542

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.000414 AC: 597 AN: 1443664 Hom.: 1 Cov.: 30 AF XY: 0.000408 AC XY: 293 AN XY: 718628

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000180 AC: 6 AN: 33386

American (AMR) AF: 0.000179 AC: 8 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38002

Middle Eastern (MID) AF: 0.00436 AC: 18 AN: 4130

European-Non Finnish (NFE) AF: 0.000487 AC: 541 AN: 1111400

Other (OTH) AF: 0.000300 AC: 18 AN: 60084

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74420

African (AFR) AF: 0.000217 AC: 9 AN: 41544

American (AMR) AF: 0.000131 AC: 2 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.361 Hom.: 6594

Bravo AF: 0.000355

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000639 AC: 3

ExAC AF: 0.000372 AC: 43

EpiCase AF: 0.000273

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	9	-	not provided (15)
3	9	1	Familial cancer of breast (13)
4	3	-	Hereditary cancer-predisposing syndrome (9)
3	1	-	CHEK2-related cancer predisposition (5)
-	3	-	not specified (3)
-	1	-	Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition (1)
-	1	-	Breast and colorectal cancer, susceptibility to (1)
-	1	-	Breast and/or ovarian cancer (1)
1	-	-	Breast carcinoma (1)
1	-	-	Breast neoplasm (1)
1	-	-	CHEK2-related disorder (1)
1	-	-	Colon cancer (1)
-	1	-	Colorectal cancer (1)
1	-	-	Familial cancer of breast;C2931456:Familial prostate cancer (1)
-	1	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.066	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		3.1
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.81
MPC		0.16
ClinPred		0.59	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.67
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs142763740; hg19: chr22-29090054; COSMIC: COSV105899907; COSMIC: COSV105899907;