chr22-28710060-C-T

Variant names:

• chr22-28710060-C-T
• rs730881687
• NM_007194.4:c.793-1G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_007194.4(CHEK2):​c.793-1G>A variant causes a splice acceptor, intron 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, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 4.76

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.033088237 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.
• 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 rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.793-1G>A		splice_acceptor_variant, intron_variant	Intron 6 of 14	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.793-1G>A		splice_acceptor_variant, intron_variant	Intron 6 of 14	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249694 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135230

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: 8 AN: 1399704 Hom.: 0 Cov.: 25 AF XY: 0.00000715 AC XY: 5 AN XY: 699566

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.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:5

Mar 08, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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; internal data). 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 31349801; internal data). For these reasons, this variant has been classified as Pathogenic. -

Jun 02, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 17, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Dec 13, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 14, 2019

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 20, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_RNA, PS4_Supporting, PM2_Supporting c.793-1G>A, located in a canonic splicing site at the kinase domain of the CHEK2 gene is predicted to alter splicing, causing the use of a cryptic splice site, removing 1 bp of exon 7 (r.793del), with a consequent frameshift (p.(Asp265Thrfs*10)). This alteration is expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay.This variant is found in 4/266602 alleles at a frequency of 0,001% in the gnomAD v2.1.1 database, non-cancer dataset (PM2_Supporting). The SpliceAI algorithm predicts that this variant causes the loss of the canonical splice acceptor site and creates a new splice acceptor site 1bp downstream. Functional analysis using either carrier peripheral blood lymphocytes mRNA or cDNA minigene constructs have revealed that this variant impacts splicing by introducing an alternative splice site 1 bp downstream leading to a frameshift, causing a protein truncation 10 amino acids downstream (PMID:31349801, PMID: 37725924) (PVS1_Observed). It has been reported in a case-control study, being found in 2 out of 60466 breast cancer-affected patients and in none of the 53461 healthy controls (PMID: 33471991), as well as in multiple cancer-affected or fulfilling hereditary cancer risk individuals (PMID: 37628581, PMID: 38898688, PMID: 36529819, PMID: 32957588, PMID: 27009842, PMID: 26681312, PMID: 27751358) (PS4_Supporting). This variant has been reported in the ClinVar database (6x pathogenic, 7x likely pathogenic), and in the LOVD (2x pathogenic). Based on currently available information, the variant c.793-1G>A should be considered a pathogenic variant, according to ACMG/AMP classification guidelines. -

Mar 27, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:3

Dec 14, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (PMID: 31349801); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast, prostate, and other cancers (PMID: 27751358, 26556299, 28888541, 29520813, 31349801, 32957588, 35734982); This variant is associated with the following publications: (PMID: 31589614, 32805687, 27751358, 26681312, 26556299, 24713400, 21876083, 25980754, 29520813, 31447099, 22419737, 19782031, 36425062, 35261632, 27009842, 31970404, 28888541, 32957588, 36493725, 31349801, 35734982) -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHEK2: PVS1, PM2, PS4:Moderate -

Feb 14, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Feb 11, 2025

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ACMG SVI adaptation criteria we chose these criteria: PVS1 (very strong pathogenic): Tayoun/Walker, PM5 (supporting pathogenic): ATM VCEP: PM5_PTCsup in addition to PVS1(RNA) -

Feb 12, 2025

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C5882668:Li-Fraumeni syndrome 2 Pathogenic:1

Jul 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.79	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

Other links and lift over

dbSNP: rs730881687; hg19: chr22-29106048; COSMIC: COSV105899856; COSMIC: COSV105899856;