22-28695254-TAGAG-TAG

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP6

The NM_007194.4(CHEK2):c.1260-14_1260-13delCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,126 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000031 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CHEK2
NM_007194.4 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 2.69

Publications

0 publications found

Variant links:

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

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 22-28695254-TAG-T is Benign according to our data. Variant chr22-28695254-TAG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 491595.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHEK2	NM_007194.4	MANE Select	c.1260-14_1260-13delCT	intron	N/A	NP_009125.1	O96017-1
CHEK2	NM_001005735.3		c.1389-14_1389-13delCT	intron	N/A	NP_001005735.1
CHEK2	NM_001438293.1		c.1353-14_1353-13delCT	intron	N/A	NP_001425222.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.1260-14_1260-13delCT	intron	N/A	ENSP00000385747.1	O96017-1
CHEK2	ENST00000382580.6	TSL:1	c.1389-14_1389-13delCT	intron	N/A	ENSP00000372023.2	O96017-9
CHEK2	ENST00000402731.6	TSL:1	c.1059-14_1059-13delCT	intron	N/A	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000307

AC:

AN:

1301744

Hom.:

AF XY:

0.00000152

AC XY:

AN XY:

656014

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30166

American (AMR)

AF:

0.00

AC:

AN:

44432

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25088

East Asian (EAS)

AF:

0.00

AC:

AN:

38984

South Asian (SAS)

AF:

0.00

AC:

AN:

82920

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5450

European-Non Finnish (NFE)

AF:

0.00000414

AC:

AN:

966416

Other (OTH)

AF:

0.00

AC:

AN:

55046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial cancer of breast (2)

Hereditary cancer-predisposing syndrome (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over