rs200432447

Positions:

Variant summary

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

The ENST00000404276.6(CHEK2):c.1555C>T(p.Arg519Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,588,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R519R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CHEK2
ENST00000404276.6 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20

Conservation

PhyloP100: 1.31

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 10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0472 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PP5

Variant 22-28687974-G-A is Pathogenic according to our data. Variant chr22-28687974-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28687974-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1555C>T	p.Arg519Ter	stop_gained	15/15	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.1555C>T	p.Arg519Ter	stop_gained	15/15	1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

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

GnomAD3 exomes

AF:

0.00000429

AC:

AN:

232840

Hom.:

AF XY:

0.00

AC XY:

AN XY:

128096

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000101

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:

0.0000111

AC:

AN:

1438324

Hom.:

Cov.:

AF XY:

0.00000698

AC XY:

AN XY:

716158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000723

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150064

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73214

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000133

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Arg519*) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the CHEK2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of CHEK2-related conditions (PMID: 25186627, 25503501, 27751358, 29020732, 29520813, 30287823, 30680046, 32761968). ClinVar contains an entry for this variant (Variation ID: 128064). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 34903604). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the nuclear localization signal (NLS) of the CHEK2 protein, which is critical for proper nuclear localization (PMID: 18004398, 12909615). While functional studies have not been performed to directly test the effect of this variant on CHEK2 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 24, 2021	- -

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 25, 2023	The CHEK2 c.1555C>T (p.Arg519*) variant is not predicted to cause nonsense-mediated decay, however it may negatively impact protein function due to the partial loss of the nuclear localization signal that is located within the truncated 25 amino acids (PMID: 24879340 (2014), 22419737 (2012), 12909615 (2003)). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32805687 (2020), 32761968 (2020), 30287823 (2018), 25503501 (2015), 25318351 (2014)), ovarian cancer (PMID: 29020732 (2018), prostate cancer (PMID: 29520813 (2018)), and colorectal cancer (PMID: 26681312 (2015)). The frequency of this variant in the general population, 0.000099 (1/10138 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2024	Nonsense variant predicted to result in protein truncation, as the last 25 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast, ovarian, prostate, and other cancers (PMID: 25503501, 25186627, 25318351, 32832836, 32761968, 35118230); Published functional studies are inconclusive: demonstrate intermediate impact on phosphorylation compared to wildtype (PMID: 34903604); This variant is associated with the following publications: (PMID: 26681312, 29520813, 12909615, 24879340, 33309985, 36243179, 25503501, 25318351, 27751358, 29020732, 18004398, 29308099, 25186627, 30680046, 30287823, 30293905, 35273153, 32805687, 32832836, 32980694, 32761968, 34204722, 32322110, 32172797, 35118230, 32019277, 36988593, 31650100, 35643632, 38575974, 22419737, 38898688, 34903604) -

Hereditary cancer-predisposing syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 12, 2022	This variant changes 1 nucleotide in exon 15 of the CHEK2 gene, creating a premature translation stop signal in the last coding exon. The mutant transcript is likely to escape nonsense-mediated decay and expressed as a truncated protein that lacks the functionally important nuclear localization signal (PMID: 12909615, 16798742, 24879340). This variant has been reported in seven individuals affected with breast cancer, including two individuals having a family history of breast or colorectal cancer (PMID: 25503501, 25318351, 30287823; Color internal data) and in an individual affected with ovarian cancer with a family history colorectal cancer (PMID: 29020732). This variant has also been reported individuals affected with uterine cancer (PMID: 30680046) and prostate cancer (PMID: 29520813), and in four unaffected individuals (PMID: 30287823). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Breast Care Center, Daerim St. Mary`s Hospital	Jul 25, 2023	The CHEK2:c.1555C>T (p.Arg519*) variant was located in the last coding exon 15 of the CHEK2 gene, which predicts a truncation to lead to a nonsense codon, resulting in a null variant. This type of variant is a known mechanism of disease. It was rarely reported in the gnomAD population database. This likely pathogenic variant was detected in a 73-year-old Korean female diagnosed with hormone-positive and invasive breast cancer. The patient had a first-degree family member with pancreatic cancer in their 70s. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jun 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 09, 2021	The p.R519* pathogenic mutation (also known as c.1555C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1555. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration occurs at the 3' terminus of theCHEK2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 25 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data; Zannini L et al. J. Biol. Chem. 2003 Oct;278:42346-51). This mutation has been reported in the literature in breast cancer and prostate cancer cohorts (Yorczyk A et al. Clin. Genet. 2015 Sep;88:278-82; Maxwell K et al. Genet. Med. 2015 Aug;17:630-8; Wu Y et al. Prostate 2018 06;78(8):607-615; Fonfria M et al. J Pers Med 2021 Jun;11(6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Li-Fraumeni syndrome 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Oct 01, 2024

Criteria applied: PVS1_STR, PS4_MOD, PM2_SUP -

Breast and/or ovarian cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 17, 2020

- -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:Li-Fraumeni syndrome 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PVS1_Strong+PM2_Supporting+PS4 -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 19, 2020

Variant summary: CHEK2 c.1555C>T (p.Arg519X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.3e-06 in 232840 control chromosomes (gnomAD). c.1555C>T has been reported in the literature in multiple individuals affected with colon cancer, prostate cancer, breast cancer and/or ovarian cancer (Yorczyk_2014, Maxwell_2014, Susswein_2015, Velho_2019, Ryu_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (1x) and likely pathogenic (5x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Breast and colorectal cancer, susceptibility to

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Jul 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Benign

0.70

MutationTaster

Benign

1.0

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

Vest4

0.79

GERP RS

3.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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