22-28725259-T-C

Position:

chr22-28725259-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong

The NM_007194.4(CHEK2):c.428A>G(p.His143Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,613,994 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 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.12

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.428A>G	p.His143Arg	missense_variant	3/15	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.428A>G	p.His143Arg	missense_variant	3/15	1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152164

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727214

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:

0.0000288

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 25, 2023	This missense variant replaces histidine with arginine at codon 143 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). This variant has been reported as defective in a yeast complementation assay (PMID: 22419737). This variant has been reported in individuals each affected with ovarian cancer (PMID: 22006311, 32546565), breast cancer (PMID: 25428789, 33471991, 36315513), and Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). 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	Jul 06, 2023	The p.H143R variant (also known as c.428A>G), located in coding exon 2 of the CHEK2 gene, results from an A to G substitution at nucleotide position 428. The histidine at codon 143 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in individuals diagnosed with ovarian cancer (Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Song H et al. J Med Genet, 2021 05;58:305-313). This alteration has also been identified in numerous breast cancer cohorts as well as unaffected control groups across studies (Churpek JE et al. Breast Cancer Res. Treat., 2015 Jan;149:31-9; Decker B et al. J Med Genet, 2017 11;54:732-741; Dorling et al. N Engl J Med. 2021 02;384:428-439; McDonald JT et al. PLoS One, 2022 Oct;17:e0273835). This alteration was also identified in an individual diagnosed with colorectal cancer (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). The p.H143R variant is located in the FHA functional domain of CHK2 and has been found to be non-functional in yeast-based in vivo functional assays (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7). 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jul 21, 2021	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 10, 2023	In the published literature, this variant has been reported in individuals with colorectal (PMID: 28944238 (2017)) and ovarian cancer (PMID: 22006311 (2011)), and suspected Lynch syndrome (PMID: 25980754 (2015)). Additionally, it has also been reported in individuals with breast cancer as well as in unaffected controls (PMIDs: 33471991 (2021), 28779002 (2017), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). Functional studies showed inconclusive results regarding the variant's impact on protein function (PMID: 22419737 (2012)), 22006311 (2011)). The frequency of this variant in the general population, 0.00002 (3/152164 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2024	Published functional studies suggest a damaging effect: loss of DNA damage response in yeast-based assays (Walsh et al., 2011; Roeb et al., 2012); Observed in individuals with a personal or family history of breast or ovarian cancer or with a Lynch syndrome-related cancer and/or polyps (PMID: 22006311, 22419737, 25428789, 25980754, 36315513, 34284872, 28944238, 28779002); 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; This variant is associated with the following publications: (PMID: 22419737, 22006311, 25980754, 25428789, 36315513, 34284872, 28779002, 19782031, 33471991, 28944238) -

Familial cancer of breast

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 143 of the CHEK2 protein (p.His143Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer, breast cancer, and suspected Lynch syndrome (PMID: 22006311, 25428789, 25980754). This variant is also known as p.His186Arg. ClinVar contains an entry for this variant (Variation ID: 142196). 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: 22006311, 22419737). 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	Mar 15, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 25, 2020

DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.428A>G, in exon 3 that results in an amino acid change, p.His143Arg. This sequence change has been previously described in some patients with breast cancer, colorectal cancer and ovarian small cell carcinoma (PMIDs: 25428789, 25980754, 22006311). This sequence change is absent from the large population databases such as ExAC and gnomAD (dbSNP rs587782300). The p.His143Arg change affects a highly conserved amino acid residue located in the forkhead-associated (FHA) domain of the CHEK2 protein that is known to be functional. In vivo functional assay in yeast showed impairs DNA damage repair activity (PMID: 22419737). In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.His143Arg substitution. This variant has been classified as a variant of unknown significance in ClinVar by other laboratories. Due to lack of more substantial evidence for its pathogenicity, the clinical significance of the p.His143Arg change remains unknown at this time. -

CHEK2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2022

The CHEK2 c.428A>G variant is predicted to result in the amino acid substitution p.His143Arg. This variant has been reported in individuals with multiple cancer types, and functional studies support its pathogenicity (Walsh et al. 2011. PubMed ID: 22006311; Churpek et al. 2015. PubMed ID: 25428789; Yurgelun et al. 2015. PubMed ID: 25980754; Roeb et al. 2012. PubMed ID: 22419737). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to insufficient functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

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

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.95

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

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.5

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.3

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

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0060

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

Polyphen

1.0

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

Vest4

0.74

MVP

0.99

MPC

0.17

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.89

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