22-28687947-C-T

Position:

chr22-28687947-C-T

Variant summary

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

The NM_007194.4(CHEK2):c.1582G>A(p.Glu528Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000576 in 1,596,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 3.65

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=0.20885828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1582G>A	p.Glu528Lys	missense_variant	15/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.1582G>A	p.Glu528Lys	missense_variant	15/15	1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152208

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:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000214

AC:

AN:

233632

Hom.:

AF XY:

0.0000234

AC XY:

AN XY:

128334

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000184

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1444092

Hom.:

Cov.:

AF XY:

0.0000501

AC XY:

AN XY:

718786

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000675

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74354

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:

0.000118

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000218

AC:

ExAC

AF:

0.00000871

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 528 of the CHEK2 protein (p.Glu528Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with diffuse large B cell lymphoma and colorectal cancer (PMID: 23960188, 28135145, 34326862). ClinVar contains an entry for this variant (Variation ID: 142361). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 17, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 29, 2016	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 21, 2022	The p.E528K variant (also known as c.1582G>A), located in coding exon 14 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1582. The glutamic acid at codon 528 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in the germline of one Chinese individual diagnosed with diffuse large B-cell lymphoma (de Miranda NF et al. J. Exp. Med. 2013 Aug;210:1729-42). In addition, this alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 03, 2021	This missense variant replaces glutamic acid with lysine at codon 528 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. An experimental functional study has been shown this variant to be neutral in a yeast based DNA damage repair assay (PMID: 30851065). This variant has been reported in individuals affected with colorectal cancer in the literature (PMID: 28135145). This variant has been identified in 8/265030 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 17, 2021	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colon cancer and lymphoma (de Miranda et al., 2013; Yurgelun et al., 2017); Published functional studies demonstrate no damaging effect: cell growth and proliferation after DNA damage similar to wild type (Delimitsou et al., 2019); This variant is associated with the following publications: (PMID: 23960188, 28135145, 28211887, 31398194, 32906215, 30851065) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 31, 2023	In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 28135145 (2017)). A yeast functional assay found that this variant had a benign effect on protein function (PMID: 30851065 (2019)). The frequency of this variant in the general population, 0.00004 (5/124096 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 05, 2021

Variant summary: CHEK2 c.1582G>A (p.Glu528Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 233632 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1582G>A has been reported in the literature as a germline variant in individuals with diffuse large B-cell lymphoma (DLBCL) and colorectal cancer (e.g. deMiranda_2013, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant showed no damaging effects in a yeast-based assay (e.g. Delimitsou_2019). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

CHEK2-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C5882668:Li-Fraumeni syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

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

Eigen

Benign

-0.040

Eigen_PC

Benign

-0.061

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

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

M_CAP

Benign

0.080

MetaRNN

Benign

0.21

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

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.0

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

MutationTaster

Benign

0.98

D;D;D;D;D;D;D;D;D;D;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.94

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

REVEL

Benign

0.14

Sift

Benign

0.034

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

Sift4G

Benign

0.13

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

Polyphen

0.88

P;P;P;.;P;D;P;D;P

Vest4

0.26

MVP

0.78

MPC

0.022

ClinPred

0.15

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.092

gMVP

0.42

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