NM_007194.4:c.853A>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_007194.4(CHEK2):c.853A>T(p.Ile285Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. I285V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52

Publications

1 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.853A>T	p.Ile285Phe	missense_variant	Exon 8 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.853A>T	p.Ile285Phe	missense_variant	Exon 8 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1407904

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701158

African (AFR)

AF:

0.00

AC:

AN:

32496

American (AMR)

AF:

0.00

AC:

AN:

41908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25452

East Asian (EAS)

AF:

0.00

AC:

AN:

39364

South Asian (SAS)

AF:

0.00

AC:

AN:

83210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1068858

Other (OTH)

AF:

0.00

AC:

AN:

58550

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:1

Nov 21, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine with phenylalanine at codon 285 of the CHEK2 protein (p.Ile285Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual undergoing Lynch syndrome genetic testing (PMID: 25980754).¬†ClinVar contains an entry for this variant (Variation ID:¬†530076). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

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

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.80

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

MetaSVM

Uncertain

-0.018

MutationAssessor

Uncertain

2.8

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

PhyloP100

2.5

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.6

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

REVEL

Uncertain

0.48

Sift

Uncertain

0.0040

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

Sift4G

Uncertain

0.0050

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

Polyphen

1.0

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

Vest4

0.82

MutPred

0.80

Loss of methylation at K287 (P = 0.1056);Loss of methylation at K287 (P = 0.1056);Loss of methylation at K287 (P = 0.1056);.;Loss of methylation at K287 (P = 0.1056);.;Loss of methylation at K287 (P = 0.1056);.;Loss of methylation at K287 (P = 0.1056);.;.;.;

MVP

0.72

MPC

0.18

ClinPred

0.97

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.82

gMVP

0.71

Mutation Taster

=52/48

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over