Genetic Variant CHEK2:p.Arg117Gly (chr22-28725338-T-C) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 18P and 1B. PS3PM1PP3_StrongPP5_Very_StrongBS2_Supporting

The NM_007194.4(CHEK2):c.349A>G(p.Arg117Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,613,986 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000183898: Multiple functional studies have found that this variant is abnormal with respect to protein stability and kinase activity (Sodha N et al. Cancer Res. 2006 Sep" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R117W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:50O:2

Conservation

PhyloP100: 1.75

Publications

115 publications found

Variant links:

COSMIC-nc: COSV104407895

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, ClinGen
Li-Fraumeni syndrome 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
hereditary breast carcinoma
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
acute myeloid leukemia
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary nonpolyposis colon cancer
Inheritance: Unknown 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: Pathogenic. The variant received 17 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000183898: Multiple functional studies have found that this variant is abnormal with respect to protein stability and kinase activity (Sodha N et al. Cancer Res. 2006 Sep;66:8966-70; Chrisanthar R et al. PLoS One. 2008 Aug;3:e3062; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Delimitsou A et al. Hum. Mutat. 2019 May;40(5):631-648; Boonen RACM et al. Cancer Res, 2022 Feb;82:615-631).; SCV000537618: "Functional studies have shown that this variant causes reduced kinase activity, reduced protein stability, incomplete phosphorylation of CHEK2 protein and defective DNA damage repair (PMID: 16835864, 16982735, 18725978, 22419737, 30851065, 34903604, 37449874)."; SCV005902003: Functional studies have shown that this variant causes reduced kinase activity, reduced protein stability, incomplete phosphorylation of CHEK2 protein, defective DNA damage repair in a yeast based assay (PMID: 16835864, PMID: 16982735, PMID: 18725978, PMID: 22419737, PMID: 30851065). Also, a recent CHEK2-complementation assay quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells has shown a deleterious effect (PMID: 37449874)(PS3).; SCV000262374: Experimental studies have shown that this missense change affects CHEK2 function (PMID: 16982735, 18725878, 22419737).; SCV000149921: Published functional studies demonstrate a damaging effect: reduced auto-phosphorylation, protein instability, impaired kinase activity, and loss of CHEK2-mediated DNA damage response (Wu 2006, Sodha 2006, Chrisanthar 2008, Roeb 2012, Delimitsou 2019).; SCV000889334: Functional studies in the published literature report this variant causes loss of CHEK2 activity (PMIDs: 30851065 (2019), 22419737 (2012), 18725978 (2008), 16982735 (2006), 16835864 (2006)).; SCV000892319: PS3:Supporting; SCV006325075: Functional studies indicate that this sequence change impacts function of CHEK2 (PMID: 16982735, 16835864, 18725978).; SCV001434869: Experimental studies are consistent with this variant resulting in disruption of CHEK2 function (PMID 16982735, 16835864, 22419737).; SCV000698796: Functional in vitro and in vivo studies showed that p.R117G is incompletely phosphorylated and is not efficiently activated in response to DNA damage, showing minimal kinase activity when studied in isolation, however, it can dimerize efficiently to CHEK2 wild-type without strongly affecting the wild-type CHEK2 activity (Roeb_2012, Chrisanthar_2008, Sodha_2006, Wu_2006).; SCV001550444: "In vitro studies have demonstrated that the Arg117Gly variant has strongly reduced kinase activity (Chrisanthar 2008). Multiple studies found that following DNA damage with ionizing radiation, the variant protein demonstrated greatly reduced CHEK2 kinase activity (Wu 2006, Roeb 2012, Le Calvez-Kelm 2011)."; SCV001737462: Several functional studies suggest that this variant is pathogenic, demonstrating a strongly reduced CHEK2-mediated DNA damage response, impaired kinase activity, and incomplete phosphorylation (PS3; PMID: 18725978, 22419737, 30851065, 16835864, 16982735).; SCV002318957: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 18725978; 16982735; 22419737)"; SCV004801674: Functional studies in cells lines demonstrated reduced protein expression and stability, and impaired phosphorylation and kinase activity of the variant protein when compared to wildtype protein. Sodha et al. 2006; Wu et al. 2006; Chrisanthar et al. 2008.; SCV000806879: Several functional studies on this variant have indicated impaired CHEK2 functions, specifically the kinase activity and DNA damage response (Chrisanthar et al. 2008. PubMed ID: 18725978; Roeb et al. 2012. PubMed ID: 22419737).

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 68 uncertain in NM_007194.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

PP5

Variant 22-28725338-T-C is Pathogenic according to our data. Variant chr22-28725338-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 128071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 13 AD,Unknown gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007194.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHEK2	NM_007194.4	MANE Select	c.349A>G	p.Arg117Gly	missense	Exon 3 of 15	NP_009125.1	O96017-1
CHEK2	NM_001005735.3		c.478A>G	p.Arg160Gly	missense	Exon 4 of 16	NP_001005735.1
CHEK2	NM_001438293.1		c.442A>G	p.Arg148Gly	missense	Exon 4 of 16	NP_001425222.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.349A>G	p.Arg117Gly	missense	Exon 3 of 15	ENSP00000385747.1	O96017-1
CHEK2	ENST00000382580.6	TSL:1	c.478A>G	p.Arg160Gly	missense	Exon 4 of 16	ENSP00000372023.2	O96017-9
CHEK2	ENST00000402731.6	TSL:1	c.349A>G	p.Arg117Gly	missense	Exon 2 of 13	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000119

AC:

AN:

251236

AF XY:

0.0000810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000193

AC:

282

AN:

1461792

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

133

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000234

AC:

260

AN:

1111952

Other (OTH)

AF:

0.000149

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.0000854

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41446

American (AMR)

AF:

0.0000655

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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:

0.000241

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (16)

Familial cancer of breast (10)

CHEK2-related cancer predisposition (8)

Hereditary cancer-predisposing syndrome (7)

CHEK2-related disorder (2)

Inherited breast cancer and ovarian cancer (2)

Malignant tumor of breast (2)

Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition (1)

Breast and/or ovarian cancer (1)

Breast cancer, susceptibility to;C3469524:Prostate cancer susceptibility (1)

Hereditary breast ovarian cancer syndrome (1)

Predisposition to cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

PhyloP100

1.7

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.4

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.85

MVP

0.98

MPC

0.17

ClinPred

0.97

GERP RS

4.8

Varity_R

0.99

gMVP

0.81

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over