rs201206424

chr22-28696960-G-Achr22-28696960-G-Cchr22-28696960-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5PP3_Moderate

The NM_007194.4(CHEK2):c.1036C>T(p.Arg346Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,612,746 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. R346H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:15

Conservation

PhyloP100: 2.78

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 Uncertain_significance. Variant got 4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-28696959-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182431.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=8, Likely_pathogenic=2, not_provided=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1036C>T	p.Arg346Cys	missense_variant	10/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.1036C>T	p.Arg346Cys	missense_variant	10/15	1	NM_007194.4	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251222

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1460714

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

726734

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000549

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

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:

0.0000697

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 346 of the CHEK2 protein (p.Arg346Cys). This variant is present in population databases (rs201206424, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer (PMID: 21244692, 27595995, 30651582, 30851065, 33128190). ClinVar contains an entry for this variant (Variation ID: 142222). 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, 36468172). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	Counsyl	Feb 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -

not provided

Pathogenic:2Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 19, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2023	Observed in individuals with breast or ovarian cancer (Zheng et al., 2018; Girard et al., 2019; Krivokuca et al., 2019; Apostolou et al., 2021; Bhai et al., 2021; Fonfria et al., 2021; Gomes et al., 2021; Guindalini et al., 2022); Published functional studies demonstrate a damaging effect: reduced cell growth rate following DNA damage (Delimitsou et al., 2019); 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: 21244692, 26787654, 22114986, 28452373, 30287823, 31050813, 28580595, 30651582, 30303537, 33128190, 34204722, 33925588, 33134171, 27595995, 30851065, 33471991, 30975761, 22419737, 19782031, 36315097, 30130155, 34326862, 36978154, 35441217, 36243179, 35264596) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 17, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 12, 2024	The p.R346C variant (also known as c.1036C>T), located in coding exon 9 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1036. The arginine at codon 346 is replaced by cysteine, an amino acid with highly dissimilar properties. In a study involving 42671 cases and 42164 controls, this variant was significantly associated with breast cancer [OR 5.06 (95% CI 1.09 to 23.5); p=0.017] (Southey MC et al. J. Med. Genet. 2016 Dec;53:800-811). In another study, this variant did not segregate with cancer in one family, but did show loss of heterozygosity in a tumor specimen (Grasel RS et al. Front Oncol, 2020 Oct;10:571330). This alteration has been identified in individuals diagnosed with breast cancer, ovarian cancer and mesothelioma (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6; Zheng Y et al. J Clin Oncol, 2018 Oct;36:2820-2825; Girard E et al. Int. J. Cancer, 2019 04;144:1962-1974; Hassan R et al. Proc Natl Acad Sci U S A, 2019 04;116:9008-9013; Krivokuca A et al. J. Hum. Genet., 2019 Apr;64:281-290; Apostolou P et al. Cancers (Basel), 2021 Apr;13:; Gomes R et al. Breast Cancer Res Treat, 2021 Feb;185:851-861). Additionally, 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 01, 2023	This missense variant replaces arginine with cysteine at codon 346 in the kinase domain 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). A functional study in human cells has shown the mutant protein to be defective in KAP1 phosphorylation and CHEK2 autophosphorylation (PMID: 37449874) and a study in yeast has shown the mutant protein to be defective in DNA damage response (PMID: 30851065). This variant has been reported individuals affected with breast cancer (PMID: 21244692, 30303537, 33128190, 33925588, 34204722), ovarian cancer (PMID: 30651582) and mesothelioma (PMID: 30975761), as well as in unaffected individuals (PMID: 30287823, 31214711, 32980694). This variant has been reported in four large breast cancer case-control studies or meta-analyses; reported in 23/73048 cases and 4/88658 unaffected controls (OR=5.85, 95%CI 2.00-16.92) (PMID: 37449874), 10/60466 cases and 2/53461 unaffected controls (OR=4.421, 95%CI 0.969-20.18) (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_00011), 9/42671 cases and 2/42164 unaffected controls (OR=5.06. 95%CI 1.09-23.5) (PMID: 27595995), and 3/1313 cases and 0/1123 unaffected controls (OR=5.91, 95%CI 0.3051 to 114.5995) (PMID: 21244692). This variant has been identified in 13/251222 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C1836482:Li-Fraumeni syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 07, 2023

- -

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.Arg346Cys variant was identified in 3 of 2606 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Le Calvez-Kelm 2011). The variant was also identified in dbSNP (ID: rs201206424) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Color Genomics, and Counsyl), and Cosmic (3x in breast, large intestine or lung tissue); it was not identified in MutDB or the Zhejiang University database. The variant was identified in control databases in 13 of 246016 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017) in the following populations: European in 10 of 111540 chromosomes (freq: 0.00009), Other in 1 of 5472 chromosomes (freq: 0.0002), East Asian in 1 of 17248 chromosomes (freq: 0.00006), and South Asian in 1 of 30776 chromosomes (freq: 0.00003); it was not observed in the African, Latino, Ashkenazi Jewish, or Finnish populations. The p.Arg346 residue is conserved across mammals and other organisms and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Molecular Oncology Research Center, Barretos Cancer Hospital

Aug 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.27

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.38

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

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.88

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.91

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

MetaSVM

Uncertain

-0.044

MutationAssessor

Uncertain

2.8

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.5

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

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.98

MVP

0.78

MPC

0.18

ClinPred

0.99

GERP RS

3.5

Varity_R

0.92

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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