rs730881684

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_007194.4(CHEK2):c.503C>T(p.Thr168Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,924 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:8

Conservation

PhyloP100: 7.12

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a domain FHA (size 62) in uniprot entity CHK2_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_007194.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.503C>T	p.Thr168Ile	missense_variant	4/15	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.503C>T	p.Thr168Ile	missense_variant	4/15	1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727208

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

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:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 19, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 08, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 14, 2023	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 168 of the CHEK2 protein (p.Thr168Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and ovarian cancer or male breast cancer (PMID: 31050813, 31409080, 35264596). ClinVar contains an entry for this variant (Variation ID: 182427). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 31050813, 31409080). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 02, 2023	This missense variant replaces threonine with isoleucine at codon 168 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies report conflicting results regarding the impact of this variant on CHEK2 phosphorylation activity (PMID: 31050813, 37449874). This variant has been reported in individuals affected with breast cancer (PMID: 31050813, 37449874) and in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000524). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 23, 2023	The p.T168I variant (also known as c.503C>T), located in coding exon 3 of the CHEK2 gene, results from a C to T substitution at nucleotide position 503. The threonine at codon 168 is replaced by isoleucine, an amino acid with similar properties. This variant was functional in an in vitro kinase assay but non-functional in a human cell-based kinase assay also measuring KAP1 phosphorylation (Kleiblová P et al. Klin Onkol, 2019;32:36-50). This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Li-Fraumeni syndrome 2

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Genetics, HCU Lozano Blesa

May 01, 2023

Variant summary: CHEK2 c.503C>T results in the replacement of Thr168 by an Ile residue (p.Thr168Ile). The variant was identified in 1 out of 396 patients analysed (freq: 0.0025, doi: 10.3389/fgene.2023.1274108). The patient was a man that developed breast cancer at the age of 57 (luminal-Her2+ tumor phenotype). A co-segregation study was done, showing that the mother and one sister developed breast cancer (BC) at the age of 72 and 64 years, respectively, and that an aunt (by the father side) developed BC at the age of 40 years. The variant was checked in the affected proband's sister, but results showed she did not carry the genetic alteration. A second sister that has not developed BC does carry the mutation. These facts prevents clearly establishing the Thr168Ile variant as a predisposition factor for BC from this study. Moreover, Thr168 appears well conserved in vertebrate species, and the replacement of a threonine by an isoleucine represents the introduction of a bulkier residue. Thr168 is located in the FHA domain, its side chain appears buried forming an apparently stabilizing local H-bond network with Asp162, Ser164, and His143, and is far from any other domain or the dimeric surface. Our in-silico study on the protein stability based on relaxation molecular dynamics simulations (doi: 10.3389/fgene.2023.1274108) indicates that Thr168Ile reduces the conformational stability of CHEK2 protein. The variant does not appear reported in gnomAD v4. Other replacements at the same position (T168N, T168P, and T168A) appear classified in ClinVar as of Uncertain Significance. However, functional studies (PMID: 31050813, 31409080) have reported impaired kinase activity for CHEK2. The metapredictor PirePred (relies on verdicts from other 15 predictor or metapredictor tools) classifies Thr168Ile as Pathogenic, whereas the AI-based predictor AlphaMissense and the ACMG classification tool Franklin suggests this variant as Likely Pathogenic. All this information, even if not conclusive, appears to indicate this variant have more chances of being Pathogenic. -

Breast and/or ovarian cancer

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast (male or female) and/or ovarian cancer, including one patient who also harbored a pathogenic variant in BRCA2 (Kleiblova et al., 2019; Guindalini et al., 2022); Published functional studies suggest a damaging effect: impaired kinase activity (Kleiblova et al., 2019); This variant is associated with the following publications: (PMID: 22419737, 19782031, 31409080, 31050813, 35264596) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;.;D;D;.;D;.;.;D;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

.;D;.;.;D;D;.;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.91

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.3

M;M;M;M;.;M;M;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.5

D;D;D;D;D;.;D;D;.;.

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0030

D;D;D;D;D;.;D;D;.;.

Sift4G

Uncertain

0.0060

D;D;D;D;D;.;D;D;D;.

Polyphen

1.0

D;D;D;D;D;D;D;.;.;.

Vest4

0.83

MutPred

0.74

Loss of disorder (P = 0.104);Loss of disorder (P = 0.104);Loss of disorder (P = 0.104);Loss of disorder (P = 0.104);.;Loss of disorder (P = 0.104);Loss of disorder (P = 0.104);.;Loss of disorder (P = 0.104);Loss of disorder (P = 0.104);

MVP

0.98

MPC

0.17

ClinPred

0.99

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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