NM_007194.4:c.1259G>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PP3_Strong

The NM_007194.4(CHEK2):c.1259G>A(p.Cys420Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000372 in 1,612,692 control chromosomes in the GnomAD database, including 1 homozygotes. 3/3 splice prediction tools predicting alterations to normal splicing. 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. C420F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7

Conservation

PhyloP100: 6.85

Publications

5 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_pathogenic. The variant received 6 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, 71 uncertain in NM_007194.4

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.1259G>A	p.Cys420Tyr	missense_variant, splice_region_variant	Exon 11 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.1259G>A	p.Cys420Tyr	missense_variant, splice_region_variant	Exon 11 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249952

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460460

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726670

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110770

Other (OTH)

AF:

0.00

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41544

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2114

Alfa

AF:

0.00

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:1Uncertain:2

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 420 of the CHEK2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CHEK2 protein. This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is present in population databases (rs578218280, gnomAD 0.0009%). This variant has been observed in individual(s) with breast cancer (PMID: 32854451). This variant is also known as c.1388G>A (p.Cys463Tyr) . ClinVar contains an entry for this variant (Variation ID: 233743). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces cysteine with tyrosine at codon 420 of the CHEK2 protein (p.Cys420Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant also falls at the last nucleotide of exon 11 of the CHEK2 coding sequence, which is part of the consensus splice site for this exon. This variant is not found in gnomAD genomes. This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 233743) with 5 submissions all of which describe it as of uncertain significance. In-silico predictions show pathogenic computational verdict based on 10 pathogenic predictions from BayesDel_addAF, DANN, EIGEN, FATHMMMKL, LIST-S2, M-CAP, MutationTaster, PrimateAI, SIFT and scSNV-Splicing vs 3 benign predictions from DEOGEN2, MVP and MutationAssessor. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098).. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 21, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Oct 31, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces cysteine with tyrosine at codon 420 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. However, this variant causes a G>T nucleotide substitution at the last nucleotide of exon 11 of the CHEK2 gene, and splice site prediction tools suggest that this variant may impact RNA splicing. This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 32854451, 37449874). This variant has been identified in 1/249952 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. -

May 30, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.C420Y variant (also known as c.1259G>A), located in coding exon 10 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1259. The amino acid change results in cysteine to tyrosine at codon 420, an amino acid with highly dissimilar properties. However, this change occurs in the last base pair of coding exon 10, which makes it likely to have some effect on normal mRNA splicing. The nucleotide and amino acid positions are highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 05;40(5):631-648). This variant was also reported as functionally impaired 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). In addition, as a missense substitution this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Li-Fraumeni syndrome

Uncertain:1

Mar 28, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Dec 06, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Sep 20, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted CHEK2 c.1259G>A at the cDNA level, p.Cys420Tyr (C420Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Cys420Tyr was not observed at a significant allele frequency in 1000 Genomes. Since Cysteine and Tyrosine differ in polarity, charge, size, or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Cys420Tyr alters a position that is conserved across species and is located in the kinase domain (Desrichard 2011, Roeb 2012). Protein-based in silico analyses predict that this variant is probably damaging to protein structure and function, and multiple splicing models predict that this variant may impact the nearby natural splice acceptor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether CHEK2 Cys420Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

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

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.64

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

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.2

L;.;L;.;L;.;L;.;.

PhyloP100

6.8

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-9.0

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

REVEL

Uncertain

0.60

Sift

Uncertain

0.0040

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0

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

Vest4

0.95

MutPred

0.49

Gain of glycosylation at S422 (P = 0.0981);.;Gain of glycosylation at S422 (P = 0.0981);.;Gain of glycosylation at S422 (P = 0.0981);.;Gain of glycosylation at S422 (P = 0.0981);.;.;

MVP

0.80

MPC

0.19

ClinPred

0.99

GERP RS

5.7

Varity_R

0.99

gMVP

0.90

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.52

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.52

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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