chr22-28687932-T-C

Position:

chr22-28687932-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The ENST00000404276.6(CHEK2):c.1597A>G(p.Thr533Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000445 in 1,596,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T533I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CHEK2
ENST00000404276.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:7

Conservation

PhyloP100: -0.633

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006747395).

BP6

Variant 22-28687932-T-C is Benign according to our data. Variant chr22-28687932-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142032.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=5, Likely_benign=6}. Variant chr22-28687932-T-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1597A>G	p.Thr533Ala	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.1597A>G	p.Thr533Ala	missense_variant	15/15	1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152202

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:

0.00346

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:

0.000141

AC:

AN:

233692

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

128342

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00172

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000367

AC:

AN:

1444110

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

718796

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00116

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000998

GnomAD4 genome

AF:

0.000118

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00347

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ExAC

AF:

0.000122

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2020	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29522266, 26260725, 28873162, 12855706, 30851065, 28580595) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 16, 2022	The frequency of this variant in the general population, 0.0017 (34/19558 chromosomes in East Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 29522266 (2018), 28580595 (2018), and 33471991 (2021)), colorectal cancer (PMIDs: 29703253 (2018) and 33563768 (2022)) and in healthy control individuals (PMIDs: 30287823 (2018) and 33471991 (2021)). Functional studies described this variant as being functional in an in vivo yeast-based growth rate assay (PMID: 30851065 (2019)) and reported normal CHEK2 autophosphorylation in an in vitro kinase assay (PMID: 12855706 (2003)). 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 11, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 07, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 24, 2021	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 01, 2022	Variant summary: CHEK2 c.1597A>G (p.Thr533Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 233692 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5.44 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. However, pseudogene interference cannot be ruled out. The variant, c.1597A>G, has been reported in the literature in one individual with a melanoma arising in a congenital nevus of Ito, however germline or somatic status was not clearly established (Tse_2016). Additionally, the variant was reported in a patient with breast cancer (Xie_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One publication reports experimental evidence showing kinase activity comparable to wild-type associated with this variant (Wu_2003) while another reports growth in yeast as comprable to positive control (Delimitsou_2019). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (four classified as VUS while four classified as likely benign). Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary breast ovarian cancer syndrome

Benign:2

Likely benign, criteria provided, single submitter	research	Cancer Genomics Group, Japanese Foundation For Cancer Research	May 01, 2019	- -
Benign, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Jan 09, 2024	. According to the ACMG standard criteria we chose these criteria: BP4 (supporting benign): REVEL: 0.073, BS1 (strong benign): popmax:EAS popmax AF:0.00345888, BS3 (strong benign): Delimitsou (2019): benign in yeast, Stolarova (2023): benign in both assays in human cells -

CHEK2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2024

The CHEK2 c.1597A>G variant is predicted to result in the amino acid substitution p.Thr533Ala. This variant has been reported in individuals with breast cancer (Table S2, Hauke et al. 2018. PubMed ID: 29522266; described as p.Thr576Ala in Table S3, Xie et al. 2018. PubMed ID: 28580595) and an individual with advanced cancer (eTable, Mandelker et al. 2017. PubMed ID: 28873162). It has been reported along with variants in other genes as a possible somatic variant in a melanoma specimen (Table 2, Tse et al. 2016. PubMed ID 26260725) and a colorectal cancer specimen (Table S2, Mei et al. 2018. PubMed ID: 29703253). Assessment using an in vivo, yeast based, functional assay suggests this variant is benign (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). This variant has been reported at a frequency of 0.17% in individuals of East Asian origin in gnomAD. However, this variant falls within a highly paralogous region and allele frequency data should be interpreted with caution. It has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/142032/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

6.8

DANN

Benign

0.82

DEOGEN2

Benign

0.11

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.73

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

M_CAP

Benign

0.027

MetaRNN

Benign

0.0067

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

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

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.52

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

REVEL

Benign

0.073

Sift

Benign

0.16

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

Sift4G

Benign

0.48

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

Polyphen

0.0020

B;B;B;.;B;B;B;B;B

Vest4

0.13

MutPred

0.086

Loss of phosphorylation at T533 (P = 0.0078);.;Loss of phosphorylation at T533 (P = 0.0078);.;Loss of phosphorylation at T533 (P = 0.0078);.;Loss of phosphorylation at T533 (P = 0.0078);.;.;

MVP

0.44

MPC

0.020

ClinPred

0.013

GERP RS

-3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.018

gMVP

0.22

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