22-28719470-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_007194.4(CHEK2):c.608A>G(p.Asp203Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000252 in 1,589,386 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D203E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 5.97

Publications

7 publications found

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 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

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 46 uncertain in NM_007194.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.608A>G	p.Asp203Gly	missense_variant	Exon 5 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 link	c.608A>G	p.Asp203Gly	missense_variant	Exon 5 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1437290

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714034

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33112

American (AMR)

AF:

0.00

AC:

AN:

42760

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25426

East Asian (EAS)

AF:

0.00

AC:

AN:

39362

South Asian (SAS)

AF:

0.00

AC:

AN:

83662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51980

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5558

European-Non Finnish (NFE)

AF:

9.12e-7

AC:

AN:

1096088

Other (OTH)

AF:

0.00

AC:

AN:

59342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41432

American (AMR)

AF:

0.0000656

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CHEK2 (p.Asp203Gly) : This variant is located in coding region of the CHEK2 gene and results from an A to G substitution at nucleotide position 608. The aspartic acid at codon 203 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in an individual with a personal history of thyroid and bilateral breast cancer and was called a variant of uncertain significance by the authors. However, this individual was also positive for another CHEK2 alteration (c.319+2T>A) that was called likely pathogenic by the authors (PMID 28608266). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (PMID 30851065). This amino acid position is highly conserved in available vertebrate species. In-silic predictions show Pathogenic computational verdict based on 10 pathogenic predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, SIFT and scSNV-Splicing vs 3 benign predictions from DEOGEN2, LIST-S2 and PrimateAI. Therefore, this variant has been classified as of uncertain significance. -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 203 of the CHEK2 protein (p.Asp203Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thyroid and breast cancer (PMID: 28608266). ClinVar contains an entry for this variant (Variation ID: 142909). 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: 30851065, 31811167, 34903604). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 31811167; internal data). 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. -

Oct 10, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Oct 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D203G variant (also known as c.608A>G), located in coding exon 4 of the CHEK2 gene, results from an A to G substitution at nucleotide position 608. The aspartic acid at codon 203 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in an individual with a personal history of thyroid and bilateral breast cancer and was called a variant of uncertain significance by the authors. However, this individual was also positive for another CHEK2 alteration (c.319+2T>A) that was called likely pathogenic by the authors (Dominguez-Valentin M et al. Fam. Cancer, 2018 01;17:141-153). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). In another functional study, this alteration was reported as having intermediate function in an mES cell-based assay of CHEK2 activity (Boonen RACM et al. Cancer Res, 2022 02;82:615-631). This variant was reported as functional 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). 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. -

Mar 07, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces aspartic acid with glycine at codon 203 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 have shown that this variant partially disrupted protein stability and kinase activity (PMID: 34903604), had a neutral effect on CHEK2 function in a yeast DNA damage repair assay (PMID: 30851065), and did not affect RNA splicing in a minigene assay (PMID: 31811167). This variant has been reported in individuals affected with breast cancer (PMID: 28608266, 34903604). One of these individuals was affected with both thyroid cancer and bilateral breast cancer (PMID 28608266). This individual also carried a pathogenic variant in the same gene that could explain the observed disease. 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. -

Sep 03, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not provided

Uncertain:2

Mar 12, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 24, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are conflicting: some suggest DNA damage response is comparable to wild type (Delimitsou et al., 2019), while others show intermediate levels of Kap1 phosphorylation (Boonen et al., 2022); Observed in individuals with personal and/or family history of breast and thyroid cancer (Dominguez-Valentin et al., 2018; Boonen et al., 2022); This variant is associated with the following publications: (PMID: 19782031, 27739435, 31811167, 31398194, 22419737, 30851065, 28608266, 34903604) -

not specified

Uncertain:1

Dec 01, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CHEK2 c.608A>G (p.Asp203Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.608A>G has been reported in the literature in an individual affected with breast- and thyroid cancer (Dominguez-Valentin_2018), however this individual also carried a likely pathogenic CHEK2 variant. In addition, the variant was also reported in cohorts of individuals affected with breast cancer (Zanti_2019, Dorling_2021). Publications also reported experimental evidence evaluating an impact on protein function, and in a yeast based DNA-damage assay the variant showed similar function to the wild type (Delimitsou_2019), while in a mouse embryonic stem cell-based system the variant resulted in "intermediate" function, based on decreased Kap1 phosphorylation, and sensitivity to DNA break induction (Boonen_2022). In addition, the variant was shown not to affect RNA splicing in a minigene assay (Dominguez-Valentin_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30851065, 34903604, 28608266, 33120919, 33471991). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Benign

0.80

DEOGEN2

Uncertain

0.42

T;.;T;T;.;T;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.82

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

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

3.3

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

PhyloP100

6.0

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.0

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

REVEL

Pathogenic

0.86

Sift

Uncertain

0.011

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

Sift4G

Uncertain

0.016

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

Polyphen

0.99

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

Vest4

0.85

MutPred

0.56

Loss of stability (P = 0.0035);Loss of stability (P = 0.0035);Loss of stability (P = 0.0035);Loss of stability (P = 0.0035);.;Loss of stability (P = 0.0035);.;Loss of stability (P = 0.0035);.;

MVP

0.97

MPC

0.17

ClinPred

0.99

GERP RS

5.4

Varity_R

0.79

gMVP

0.73

Mutation Taster

=14/86

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over