22-28734576-G-C

Variant names:

Variant summary

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

The NM_001257387.2(CHEK2):c.-632C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,852 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: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

CHEK2
NM_001257387.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.92

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=0.21909216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.146C>G	p.Ser49Cys	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.146C>G	p.Ser49Cys	missense_variant	Exon 2 of 15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151960

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727246

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:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74188

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Dec 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S49C variant (also known as c.146C>G), located in coding exon 1 of the CHEK2 gene, results from a C to G substitution at nucleotide position 146. The serine at codon 49 is replaced by cysteine, an amino acid with dissimilar properties. This alteration was reported as functional 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). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

May 13, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Familial cancer of breast

Uncertain:2

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 serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 49 of the CHEK2 protein (p.Ser49Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of breast cancer (PMID: 36315513). ClinVar contains an entry for this variant (Variation ID: 182444). 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. 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. -

Feb 14, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Sep 22, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted CHEK2 c.146C>G at the cDNA level, p.Ser49Cys (S49C) at the protein level, and results in the change of a Serine to a Cysteine (TCC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Ser49Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Ser49Cys occurs at a position that is highly conserved across species and is located in the SQ/TQ cluster domain (Desrichard 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CHEK2 Ser49Cys is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

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

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.84

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

M_CAP

Benign

0.047

MetaRNN

Benign

0.22

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

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.2

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

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.6

N;N;N;N;N;.;N;N;N;N;N;.;N

REVEL

Benign

0.12

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.015

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

Polyphen

0.96

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

Vest4

0.20

MutPred

0.13

Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);

MVP

0.97

MPC

0.16

ClinPred

0.80

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.30

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