22-28710060-C-T

Position:

chr22-28710060-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePP3_StrongPP5_Very_Strong

The NM_007194.4(CHEK2):c.793-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000572 in 1,399,704 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 4.76

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.03247549 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4, offset of 1, new splice context is: gttattctgtttatcaaaAGacc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 22-28710060-C-T is Pathogenic according to our data. Variant chr22-28710060-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28710060-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.793-1G>A		splice_acceptor_variant		ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.793-1G>A		splice_acceptor_variant		1	NM_007194.4	P2	O96017-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249694

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000572

AC:

AN:

1399704

Hom.:

Cov.:

AF XY:

0.00000715

AC XY:

AN XY:

699566

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000901

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000378

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 02, 2017	This c.793-1G>A variant in the CHEK2 gene has not been observed in our cohort database nor has been detected in the ExAC database. This variant was however reported in ClinVar but the clinical presentation of the patients was not available (SCV000210975.9, SCV000273338.2). This variant affect the invariant acceptor splice site of intron 6 of the CHEK2 gene. While not clinically validated, computer-based algorithms predict this c.793-1G>A change to affect splicing by creating an alternative splice site 1bp downstream and thus creating a frameshift. This variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change affects an acceptor splice site in intron 6 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs730881687, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with breast cancer and prostate cancer (PMID: 26681312, 27751358, 29520813, 31349801; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182430). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 31349801; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 08, 2023	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 15, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 17, 2018	- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 13, 2023	This variant causes a G>A nucleotide substitution at the -1 position of intron 6 of the CHEK2 gene. Splice site prediction tools suggest that this variant may abolish the canonical splice acceptor site and create a new splice acceptor one basepair downstream. RNA studies have confirmed this prediction, with the variant resulting in the deletion of one nucleotide from the mRNA and a frameshift and premature termination codon within exon 7 of the protein (p.Asp265Thrfs*10) (PMID: 31349801, 37725924). This variant has been reported in individuals affected with breast cancer (PMID: 26556299, 26681312, 27751358, 31349801, 36529819) and prostate cancer (PMID: 29520813) in the literature. This variant has been reported in a homozygous individual with a personal and family history of cancer and multiple cytogenetic anomalies (PMID: 36529819). This variant has been identified in 4/249694 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Mar 14, 2019	This sequence change occurs 1 base before exon 7 of the CHEK2 gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083; PMID: 24713400). This mutation has been reported in individuals who underwent genetic testing for the risk of hereditary cancer, including breast cancer (PMID: 27751358). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this change disrupts the wild type acceptor site and activates an intronic cryptic splice acceptor 1 bp downstream, thus creating a frameshift. Experimental analysis in patient-derived leukocytes using RT-PCR of mRNA followed by cDNA sequencing showed that this variant affects splicing by creating an alternative splice site 1 bp downstream which results in a frameshift effect and the generation of a premature translation stop signal 10 amino acid residues later, and is predicted to result in a truncated protein. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 27, 2023	The c.793-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 6 of the CHEK2 gene. One study identified this alteration in 1/703 patients with lethal prostate cancer and 0/1455 patients with localized prostate cancer (Wu Y et al. Prostate, 2018 Jun;78:607-615). This alteration has also been detected in multiple individuals undergoing multi-gene panel testing (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32; Leedom TP et al. Cancer Genet. 2016 Sep;209:403-407). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Agiannitopoulos K et al. BMC Med. Genet., 2019 07;20:131). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 14, 2022	This variant disrupts a canonical splice-acceptor site and interferes with normal CHEK2 mRNA splicing. The frequency of this variant in the general population, 0.00012 (4/34412 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 26681312 (2015)), prostate cancer (PMID: 29520813 (2018)), and neuroblastoma (PMID: 27009842 (2016)), as well as an individual who underwent genetic testing for hereditary cancer risk (PMID: 31349801 (2019)). Based on the available information, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2023	Canonical splice site variant demonstrated to result in aberrant splicing, leading to protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Agiannitopoulos et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast, prostate, and other cancers (Leedom et al., 2016; Schrader et al., 2016; Lilyquist et al., 2017; Wu et al., 2018, Agiannitopoulos et al., 2019; Germani et al., 2020); This variant is associated with the following publications: (PMID: 31589614, 32805687, 27751358, 26681312, 26556299, 24713400, 21876083, 25980754, 29520813, 31447099, 22419737, 19782031, 36425062, 35261632, 27009842, 31349801, 31970404, 28888541, 32957588) -

Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C5882668:Li-Fraumeni syndrome 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.79

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D

GERP RS

5.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.92

Position offset: -2

DS_AL_spliceai

0.99

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over