chr22-28689217-T-C

Position:

chr22-28689217-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The ENST00000404276.6(CHEK2):c.1462-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000788 in 1,395,962 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: 0.0000079 ( 0 hom. )

Consequence

CHEK2
ENST00000404276.6 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.68

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:

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ACMG classification

Classification made for transcript

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 0.04901961 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4, offset of -33, new splice context is: aggagtttattatccttcAGaca. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP5

Variant 22-28689217-T-C is Pathogenic according to our data. Variant chr22-28689217-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1462-2A>G		splice_acceptor_variant		ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.1462-2A>G		splice_acceptor_variant		1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000429

AC:

AN:

233334

Hom.:

AF XY:

0.00

AC XY:

AN XY:

128290

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000922

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000788

AC:

AN:

1395962

Hom.:

Cov.:

AF XY:

0.00000860

AC XY:

AN XY:

697842

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000103

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 10, 2022	This variant causes an A to G nucleotide substitution at the -2 position of intron 13 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in several individuals affected with breast cancer (PMID: 30128536, Color internal data) and in an unaffected individual from a breast cancer case-control study (PMID: 31263054). This variant has been identified in 1/233334 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although functional consequence of this variant has not yet been demonstrated, observation of this rare variant and other c.1462-1G>A variant that impacts the same splice site (ClinVar variation ID: 410026) in individuals affected with CHEK2-related cancers suggest that this variant may be associated with disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 02, 2024	The c.1462-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 13 in the CHEK2 gene. In one study, this alteration was detected in one patient with breast cancer from a cohort of 11416 patients with breast and/or ovarian cancer and was not detected in 3988 control subjects from the United States (Lu HM et al. JAMA Oncol, 2019 01;5:51-57). In another study, this alteration was not detected in 1434 cases of invasive lobular breast cancer or 368 cases of LCIS but was detected in 1/1611 control individuals from the United Kingdom (Petridis C et al. Cancer Epidemiol. Biomarkers Prev., 2019 Jul;28:1162-1168). This nucleotide position is highly conserved in available vertebrate species. 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. 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial cancer of breast

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2023	This sequence change affects an acceptor splice site in intron 13 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 (rs587782575, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with clinical features of CHEK2-related conditions (PMID: 24763289, 27751358, 30128536). ClinVar contains an entry for this variant (Variation ID: 142596). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (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	Baylor Genetics	Feb 15, 2022	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

CHEK2: PVS1:Strong, PM2, PS4:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

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

GERP RS

5.5

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AL_spliceai

1.0

Position offset: -2

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