22-28695789-C-T

Position:

chr22-28695789-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_007194.4(CHEK2):c.1180G>A(p.Glu394Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,826 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 Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:11

Conservation

PhyloP100: 6.85

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:

CHEK2 (HGNC:):

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1180G>A	p.Glu394Lys	missense_variant	11/15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.1180G>A	p.Glu394Lys	missense_variant	11/15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

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

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251066

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461598

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

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

Alfa

AF:

0.0000480

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 28, 2023	This missense variant replaces glutamic acid with lysine at codon 394 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown this variant to be damaging to protein function in in vitro and cell based kinase assays (PMID: 31050813, 33606978) and in a DNA damage repair assay in yeast (PMID: 30851065). This variant has been reported in one individual each affected with breast cancer (PMID: 31050813), prostate cancer (PMID: 37842866) and breast, ovarian or pancreatic cancer (PMID: 34026625). This variant also has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000345). This variant has been identified in 5/251066 chromosomes 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	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 07, 2023	The p.E394K variant (also known as c.1180G>A), located in coding exon 10 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1180. The glutamic acid at codon 394 is replaced by lysine, an amino acid with similar properties. This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). Additionally, this alteration was identified in 1/1928 breast and/or ovarian cancer patients and 0/3360 population-matched controls. In a functional assay included in this study, this variant was reported as non-functional in both in vitro kinase and human-cell based assays of KAP1 phosphorylation (Kleiblova P et al. Int. J. Cancer, 2019 Oct;145:1782-1797). This alteration was reported as functionally impaired in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). Finally, this variant demonstrated enrichment behavior in the presence of doxorubicin and olaparib and reduced expression of CHK2 in a drug sensitivity assay performed in MCF10A -BE3 cells with CRISPR-introduced variants (Cuella-Martin R et al. Cell, 2021 Feb;184:1081-1097.e19). 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. -

Familial cancer of breast

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 394 of the CHEK2 protein (p.Glu394Lys). This variant is present in population databases (rs587780169, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 30303537, 31050813, 31784482, 35220195). This variant is also known as c.1309G>A (p.Glu437Lys). ClinVar contains an entry for this variant (Variation ID: 128048). 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 have shown that this missense change affects CHEK2 function (PMID: 30851065, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 31, 2023	a variant of uncertain significance in the CHEK2 gene. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 394 of the CHEK2 protein (p.Glu394Lys). This variant is present in population databases (rs587780169, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 30303537, 31050813, 31784482). ClinVar contains an entry for this variant (Variation ID: 128048).this alteration is predicted to be pathogenic computational verdict based on 20 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL , SIFT , CADD, MutPred , LRT , SIFT4G , REVEL , MetaRNN and Polyphen2 vs non benign prediction. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 30851065, 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. pathogenic/likely pathogenic variants in the CHEK2 gene cause autosomal dominant susceptibility to breast cancer (OMIM 114480). -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

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

Dec 19, 2023

. According to the ACMG standard criteria we chose these criteria: PS3 (strong pathogenic): Deleterious in : Stolarova et al 2023 (PMID: 37449874), Kleiblova et al 2019 (PMID: 31050813), Delimitsou et al 2019 (PMID: 30851065), PM2 (supporting pathogenic): popmax: AFR popmax AF:2.41220e-05, PP3 (supporting pathogenic): REVEL: 0.864, BayesDEL:0.394329 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 21, 2023

Variant summary: CHEK2 c.1180G>A (p.Glu394Lys) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251066 control chromosomes. c.1180G>A has been reported in the literature as a VUS in settings of multigene panel testing and in case control studies of individuals affected with breast cancer (example, Doddato_2021, Girard_2019, Bora_2022, Kleibova_2019). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in in-vivo characterization as damaging in a yeast functional assay evaluating ability to repair methylmethanesulfonate (MMS) induced DNA damage (example, Delimitsou_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 24, 2021

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate damaging effects: Reduced kinase activity and DNA damage response (Delimitsou 2019, Kleiblova 2019); Observed in an individual with breast cancer (Kleiblova 2019); This variant is associated with the following publications: (PMID: 18571837, 24573554, 22578220, 23856246, 21765476, 30851065, 31050813, 30303537, 31398194) -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The CHEK2 p.Glu394Lys variant was not identified in the literature nor was it identified in the MutDB, or Zhejiang Colon Cancer Database. The variant was also identified in the following databases: dbSNP (ID: rs587780169) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified uncertain significance by GeneDx, Ambry Genetics and Invitae), Clinvitae (3x), Cosmic (2x in a malignant melanoma and lymphoid neoplasm), and in control databases in 5 of 245908 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Observations by population include European Non-Finnish in 3 of 111386 chromosomes (freq: 0.00003), and Ashkenazi Jewish in 2 of 9846 chromosomes (freq: 0.0002); it was not observed in the African, â€šÃ„ÃºOtherâ€šÃ„Ã¹, Latino, East Asian, European Finnish, and South Asian populations. The p.Glu394 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Lys variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

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

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.97

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

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.8

H;.;H;.;H;.;H;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.9

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

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.99

MutPred

0.91

Gain of methylation at E394 (P = 0.0034);.;Gain of methylation at E394 (P = 0.0034);.;Gain of methylation at E394 (P = 0.0034);.;Gain of methylation at E394 (P = 0.0034);.;.;

MVP

0.95

MPC

0.17

ClinPred

1.0

GERP RS

5.7

Varity_R

0.99

gMVP

0.98

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