22-28695839-T-C

Position:

chr22-28695839-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_007194.4(CHEK2):c.1130A>G(p.Glu377Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,730 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E377D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10B:1

Conservation

PhyloP100: 5.23

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 Uncertain_significance. Variant got 1 ACMG points.

PM1

In a region_of_interest T-loop/activation segment (size 26) in uniprot entity CHK2_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_007194.4

BP4

Computational evidence support a benign effect (MetaRNN=0.335496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1130A>G	p.Glu377Gly	missense_variant	11/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.1130A>G	p.Glu377Gly	missense_variant	11/15	1	NM_007194.4	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250492

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135598

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000144

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10Benign:1

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	Baylor Genetics	Mar 21, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 29, 2016	- -
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	Invitae	Dec 15, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 377 of the CHEK2 protein (p.Glu377Gly). This variant is present in population databases (rs560973106, gnomAD 0.01%). 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: 128045). 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. 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. -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 29, 2022	This missense variant replaces glutamic acid with glycine at codon 377 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). Functional studies have reported that this variant has a neutral impact on protein function in a yeast complementation assay (PMID: 30851065) and does not affect RNA splicing (PMID: 31843900). This variant has been reported in two individuals affected with breast cancer (PMID: 29522266; Lovejoy et al., Austin J Cancer Clin Res. 2018; 5(1): 1082), as well as in an individual age 70 years or older lacking personal history of cancer (https://whi.color.com/variant/22-29091827-T-C). This variant has been identified in 7/250492 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	Apr 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 25, 2023	The p.E377G variant (also known as c.1130A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1130. The glutamic acid at codon 377 is replaced by glycine, an amino acid with similar properties. 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 alteration was detected in 0X/1054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 1/1189 controls (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358). This amino acid position is highly 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. -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2023	Variant summary: CHEK2 c.1130A>G (p.Glu377Gly) results in a non-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 2.8e-05 in 250492 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1130A>G has been reported in the literature without strong evidence for causality (Casadei_2019). Experimental studies have reported the variant to have no impact on function or splicing (Delimitsou_2019, Casadei_2019). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six submitters classified the variant as VUS while one classified as benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Benign, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 11, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 12, 2023

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; Published functional studies suggest no damaging effect: growth rate similar to wild type in yeast-based assays and no effect on splicing (Casadei et al., 2019; Delimitsou et al., 2019); Observed in individuals with a personal and/or family history of breast and other cancers, as well as in healthy controls (Hauke et al., 2018; Casadei et al., 2019; Lovejoy et al., 2018; Weitzel et al., 2019); This variant is associated with the following publications: (PMID: 29522266, 30851065, 31843900, 22419737, 19782031, Lovejoy2018, 31206626) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

0.0021

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

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

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.048

MetaRNN

Benign

0.34

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

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.90

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.2

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

REVEL

Uncertain

0.39

Sift

Benign

0.044

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

Sift4G

Uncertain

0.022

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

Polyphen

0.95

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

Vest4

0.56

MutPred

0.41

Loss of solvent accessibility (P = 0.0477);.;Loss of solvent accessibility (P = 0.0477);.;Loss of solvent accessibility (P = 0.0477);.;Loss of solvent accessibility (P = 0.0477);.;.;

MVP

0.78

MPC

0.026

ClinPred

0.62

GERP RS

5.9

Varity_R

0.49

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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