rs1060502696

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007194.4(CHEK2):c.115T>C(p.Ser39Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 3.07

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26039103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.115T>C	p.Ser39Pro	missense_variant	Exon 2 of 15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 link	c.115T>C	p.Ser39Pro	missense_variant	Exon 2 of 15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cancer of breast

Uncertain:2

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 39 of the CHEK2 protein (p.Ser39Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 410024). 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: 37449874). 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 11, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Oct 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with proline at codon 39 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). In CHEK2-complementation assays in human CHEK2-knockout cells, this variant did not impact CHK2 autophosphorylation or KAP1 phosphorylation (PMID: 37449874). This variant has been reported in two large breast cancer case-control meta analyses; in 1/73048 cases and 1/88658 controls (PMID: 37449874), and 4/60466 cases and 0/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000254). This variant has not been identified 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. -

Jun 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S39P variant (also known as c.115T>C), located in coding exon 1 of the CHEK2 gene, results from a T to C substitution at nucleotide position 115. The serine at codon 39 is replaced by proline, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 Nov;54:732-741). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

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

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.75

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

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.26

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

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

2.0

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

PrimateAI

Benign

0.45

PROVEAN

Benign

0.030

N;N;N;N;N;.;N;N;N;N;D;.;.

REVEL

Benign

0.18

Sift

Uncertain

0.025

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

Sift4G

Benign

0.26

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

Polyphen

0.99

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

Vest4

0.40

MutPred

0.20

Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);

MVP

0.97

MPC

0.067

ClinPred

0.75

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.33

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

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