chr22-28725241-A-G

Variant names:

• chr22-28725241-A-G
• rs560596101
• NM_007194.4:c.444+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007194.4(CHEK2):​c.444+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHEK2 NM_007194.4 splice_donor, intron
• Scores: Splicing: ADA: 0.8166
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.10
• Publications: 3 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
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• acute myeloid leukemia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 9.4, offset of 4, new splice context is: cagGTaatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-28725241-A-G is Pathogenic according to our data. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725241-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 422638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.444+2T>C		splice_donor_variant, intron_variant	Intron 3 of 14	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.444+2T>C		splice_donor_variant, intron_variant	Intron 3 of 14	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251280 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:4

Jun 23, 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. -

Sep 17, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 3 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 not present in population databases (gnomAD no frequency).This nucleotide position is highly conserved ( PhyloP=6.76) . This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 422638) classified as pathogenic . Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 12533788). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 3 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 422638). 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: 12533788; internal data). For these reasons, this variant has been classified as Pathogenic. -

Aug 24, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Nov 08, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge; Also known as c.573+2T>C or IVS2+2T>C -

Mar 04, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHEK2 c.444+2T>C variant disrupts a canonical splice-donor site and is predicted to interfere with normal CHEK2 mRNA splicing. This variant has been reported in the published literature in an individual with breast cancer (PMID: 35220195 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 06, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.444+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 2 in the CHEK2 gene. This alteration was identified in a cohort of 2508 individuals who underwent multi-gene hereditary cancer panel testing and were found to have at least one pathogenic or likely pathogenic variant in CHEK2 (Sutcliffe EG et al. Cancer Genet, 2020 08;246-247:12-17). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however direct evidence is insufficient at this time. 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. As such, this alteration is classified as likely pathogenic. -

Jan 20, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a T to C nucleotide substitution at the +2 position of intron 3 of the CHEK2 gene, changing a GT donor site to a GC donor site. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing, potentially utilizing a cryptic GT donor site 4 nucleotides downstream. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. Different variants affecting the same splice donor, c.444+1G>A and c.444+1G>C, c.444+1G>T, c.444+1del are known to be disease-causing (ClinVar variation ID: 928268, 419303, 128075, 126914). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. -

Familial cancer of breast;C0376358:Prostate cancer;C0585442:Bone osteosarcoma;C5882668:CHEK2-related cancer predisposition Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: 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	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	34
DANN	Benign	0.79
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		7.1
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Benign	0.42
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.94		Position offset: -2
DS_DL_spliceai		0.98		Position offset: 2

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

Other links and lift over

dbSNP: rs560596101; hg19: chr22-29121229;