22-28699915-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_007194.4(CHEK2):c.931G>A(p.Asp311Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. D311G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:2

Conservation

PhyloP100: 2.27

Publications

8 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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26310205).

BS2

High AC in GnomAdExome4 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.931G>A	p.Asp311Asn	missense_variant	Exon 9 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.931G>A	p.Asp311Asn	missense_variant	Exon 9 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152164

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251414

AF XY:

0.0000294

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:

0.0000615

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461758

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111908

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:5

Mar 09, 2023

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 29, 2016

Counsyl

Significance:Uncertain significance

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. -

Mar 19, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 311 of the CHEK2 protein (p.Asp311Asn). This variant is present in population databases (rs587782347, gnomAD 0.005%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 21244692, 25186627, 26976419, 34371384). This variant is also known as c.1060G>A p.Asp354Asn. ClinVar contains an entry for this variant (Variation ID: 142266). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065). 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 aspartic acid with asparagine at codon 311 of the CHEK2 protein (p.Asp311Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant has been reported in individuals affected with breast cancer (PMID: 21244692, 26976419). ClinVar contains an entry for this variant (Variation ID: 142266) with 5 submissions describing this variant as of uncertain significance. This variant has been reported not to substantially affect CHEK2 protein function (PMID: 30851065). In-silico prediction show benign computational verdict based on 7 benign predictions from BayesDel_addAF, DEOGEN2, EIGEN, MVP, MutationAssessor, PrimateAI and REVEL vs 6 pathogenic predictions from DANN, FATHMM-MKL, LIST-S2, M-CAP, MutationTaster and SIFT. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:3Benign:1

Jul 07, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHEK2 c.931G>A (p.Asp311Asn) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 26976419 (2016)21244692 (2011)) as well as in a breast cancer case and a reportedly healthy individual in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). Additionally, a functional study have reported inconclusive results on the effect this variant has on protein function (PMID: 30851065 (2019)). The frequency of this variant in the general population, 0.000062 (7/113748 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jan 13, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with breast cancer (PMID: 21244692, 26976419); Published functional studies demonstrate no damaging effect: classified as having a benign effect based on in vivo yeast-based assays (PMID: 30851065); 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, 26976419, 26787654, 33471991, 19782031, 22419737, 30851065) -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CHEK2: BP1, BP4, BS3:Supporting -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

May 12, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces aspartic acid with asparagine at codon 311 of the CHEK2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. Experimental studies of DNA damage repair in yeast have not demonstrated a damaging effect of this variant (PMID: 30851065). This variant has been reported in individuals affected with hereditary breast cancer in the literature (PMID: 21244692, 26976419, 33471991). This variant has been identified in 8/251414 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. -

Feb 26, 2025

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. -

Dec 17, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not specified

Uncertain:2

Dec 01, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CHEK2 c.931G>A (p.Asp311Asn) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) 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 3.2e-05 in 251414 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.931G>A has been reported in the literature as a VUS in settings of single/multigene panel testing among individuals affected with breast/ovarian cancer (example, Le Calvez-Kelm_2011, Tung_2015, Tung_2016, Bono_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant based on the ability to repair methyl-methanesulfonate (MMS) induced DNA damage and resume cell growth and proliferation in a yeast based functional assay (Delimtsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 21244692, 25186627, 26976419, 30851065, 34371384). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary nonpolyposis colon cancer

Uncertain:1

Nov 06, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Prostate cancer;C0585442:Bone osteosarcoma;C5882668:CHEK2-related cancer predisposition

Uncertain:1

Apr 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

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

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.095

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.95

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

M_CAP

Benign

0.027

MetaRNN

Benign

0.26

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

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

PhyloP100

2.3

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.7

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

REVEL

Benign

0.11

Sift

Benign

0.087

T;T;T;.;T;T;.;T;T;D;.;T

Sift4G

Benign

0.29

T;T;T;.;T;T;.;T;T;D;.;.

Polyphen

0.0050

B;P;B;.;B;B;B;P;P;.;.;.

Vest4

0.47

MutPred

0.65

Gain of methylation at K312 (P = 0.0619);Gain of methylation at K312 (P = 0.0619);Gain of methylation at K312 (P = 0.0619);.;Gain of methylation at K312 (P = 0.0619);.;Gain of methylation at K312 (P = 0.0619);.;Gain of methylation at K312 (P = 0.0619);.;.;.;

MVP

0.74

MPC

0.022

ClinPred

0.15

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.43

Mutation Taster

=63/37

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over