22-28725277-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BP4_ModerateBP6BS2_Supporting

The NM_007194.4(CHEK2):c.410G>A(p.Arg137Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R137G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:20

Conservation

PhyloP100: 1.15

Publications

30 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: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 55 uncertain in NM_007194.4

BP4

Computational evidence support a benign effect (MetaRNN=0.09524587).

BP6

Variant 22-28725277-C-T is Benign according to our data. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073. Variant chr22-28725277-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 128073.

BS2

High AC in GnomAd4 at 18 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.410G>A	p.Arg137Gln	missense_variant	Exon 3 of 15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 link	c.410G>A	p.Arg137Gln	missense_variant	Exon 3 of 15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000175

AC:

AN:

251312

AF XY:

0.000184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000115

AC:

168

AN:

1461808

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.000425

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000112

AC:

125

AN:

1111968

Other (OTH)

AF:

0.000315

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000118

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41436

American (AMR)

AF:

0.000197

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000139

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:20

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CHEK2: BP4, BS3:Supporting -

Nov 11, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 08, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial cancer of breast

Benign:5

Mar 09, 2023

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2016

Counsyl

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 27, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CHEK2 c.410G>A (p.Arg137Gln) results in a conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 270830 control chromosomes, predominantly at a frequency of 0.00049 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Breast Cancer phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.410G>A has been reported in the literature in individuals affected with Breast Cancer (example, Bell_2007, Desrichard_2011, LeCalvez-Kelm_2011, Sodha_2002, Yorczyk_2014, Tung_2016, Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. At-least two co-occurrences with other pathogenic variant(s) have been observed at our laboratory (BRCA1 c.1960A>T, p.Lys654X; APC c.4647delA, p.Glu1550fs), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function (example, Bell_2007, Desrichard_2011, Roeb_2012, Sodha_2006, Delimitsou_2019). These results showed no damaging effect of this variant (expression, stability, kinase activity and yeast-based functional assay based on ability to repair MMS induced DNA damage and resume cell growth and proliferation). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Oct 13, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 18, 2019

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CHEK2-related cancer predisposition

Uncertain:1Benign:2

Jun 29, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Feb 16, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Nov 16, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Breast and/or ovarian cancer

Benign:1

Jan 26, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.23

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

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.057

MetaRNN

Benign

0.095

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.59

N;N;N;N;.;N;N;.;.;.;.;.

PhyloP100

1.2

PrimateAI

Benign

0.32

PROVEAN

Benign

0.38

N;N;N;N;N;.;N;N;N;.;.;.

REVEL

Uncertain

0.51

Sift

Benign

0.55

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

Sift4G

Benign

0.89

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

Polyphen

0.027

B;B;B;B;B;B;B;.;.;.;.;.

Vest4

0.24

MVP

0.95

MPC

0.021

ClinPred

0.022

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.062

gMVP

0.25

Mutation Taster

=84/16

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over