22-28734565-A-T

Position:

chr22-28734565-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_007194.4(CHEK2):c.157T>A(p.Ser53Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,613,876 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S53C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1O:1

Conservation

PhyloP100: 5.92

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 -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31754956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.157T>A	p.Ser53Thr	missense_variant	2/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.157T>A	p.Ser53Thr	missense_variant	2/15	1	NM_007194.4	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251418

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151982

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74200

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000657

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

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:4Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2023	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 53 of the CHEK2 protein (p.Ser53Thr). This variant is present in population databases (rs371657037, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilms tumor (PMID: 30344923). ClinVar contains an entry for this variant (Variation ID: 133888). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 11, 2016	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 19, 2024	The p.S53T variant (also known as c.157T>A), located in coding exon 1 of the CHEK2 gene, results from a T to A substitution at nucleotide position 157. The serine at codon 53 is replaced by threonine, an amino acid with similar properties. This alteration was detected by genome sequencing in an ancestrally diverse cohort of 681 healthy individuals (Bodian DL et al. PLoS One. 2014 Apr 11;9(4):e94554). This alteration was seen in 0/732 breast cancer patients, 0/189 colorectal cancer patients and 1/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). In another study, this variant was reported in 5/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). 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(16):3037-3050). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 24, 2023	This missense variant replaces serine with threonine at codon 53 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ovarian cancer (DOI: 10.26650/experimed.1187969) or breast cancer (PMID: 33471991), but also in control individuals (PMID: 24728327, 32658311, 33471991). This variant has been identified in 12/251418 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. -

not specified

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 12, 2023	Variant summary: CHEK2 c.157T>A (p.Ser53Thr) 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 4.8e-05 in 251418 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.00031), allowing no conclusion about variant significance. c.157T>A has been reported in the literature in individuals affected with breast cancer (e.g. Dorling_2021, de Oliveira_2022) and also in unaffected controls (e.g. Bodian_2014, Ackay_2021, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been reported in an individual with a personal and family history of breast cancer (BRCA1 c.5074+2T>C; de Oliveira_2022), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 24728327, 30344923, 33471991, 35534704). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Eight submitters have classified the variant as uncertain significance and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

CHEK2-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:1

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; Identified in individuals with breast or ovarian cancer, but also present in unaffected controls (Bodian et al., 2014; Akcay et al., 2020; Dorling et al., 2021; Ates et al., 2022); This variant is associated with the following publications: (PMID: 31398194, 30344923, 33471991, 24728327, 32658311, 22419737, 22114986, 11733767, Ates2022[Article]) -

Familial cancer of breast;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

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

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

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.61

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

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.32

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

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.2

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.1

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

REVEL

Benign

0.17

Sift

Benign

0.43

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

Sift4G

Benign

0.15

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

Polyphen

0.96

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

Vest4

0.41

MVP

0.97

MPC

0.15

ClinPred

0.55

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.34

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