22-28687962-G-A

Position:

chr22-28687962-G-A

Variant summary

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

The NM_007194.4(CHEK2):c.1567C>T(p.Arg523Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000294 in 1,596,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.51

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=0.13364786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1567C>T	p.Arg523Cys	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.1567C>T	p.Arg523Cys	missense_variant	15/15	1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD3 exomes

AF:

0.0000343

AC:

AN:

233364

Hom.:

AF XY:

0.0000312

AC XY:

AN XY:

128244

show subpopulations

Gnomad AFR exome

AF:

0.000137

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0000660

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000276

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000312

AC:

AN:

1443868

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

AN XY:

718664

show subpopulations

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000218

AC:

ExAC

AF:

0.0000261

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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	Dec 31, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 523 of the CHEK2 protein (p.Arg523Cys). 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 suspected Lynch syndrome and breast and/or cervical cancer (PMID: 25980754, 28503720, 30287823). ClinVar contains an entry for this variant (Variation ID: 141007). 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	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 05, 2017	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 20, 2022	This missense variant replaces arginine with cysteine at codon 523 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have demonstrated a neutral impact of this variant in DNA repair assays (PMID: 30851065). This variant has been reported in individuals affected with hereditary cancer (PMID: 25980754), and breast cancer (PMID: 28503720, 30287823). This variant has been identified in 9/264762 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The poor conservation of arginine at this position and no significant impact on CHEK2 function in experimental studies indicate that this variant is unlikely to be disease-causing. However, the available clinical 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	Feb 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 06, 2023	The p.R523C variant (also known as c.1567C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1567. The arginine at codon 523 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in carriers and controls from studies of prostate, and breast and/or ovarian cancer cohorts (Rummel SK et al. Breast Cancer Res Treat, 2017; Momozawa Y et al. Nat Commun, 2018 Oct;9:4083; Aug;164:593-601; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Vargas-Parra G et al. Hum Mutat, 2020 Dec;41:2128-2142; Dorling et al. N Engl J Med. 2021 02;384:428-439). 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 poorly 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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 14, 2023	In the published literature, this variant has been reported in individuals with Lynch syndrome (PMID: 25980754 (2015)), breast cancer (PMID: 30287823 (2020)), and hereditary cancer (PMID: 32906215 (2018)). Additionally, a functional study suggests that the variant is not damaging to CHEK2 protein expression or function (PMID: 30851065 (2019)). The frequency of this variant in the general population, 0.000086 (2/23334 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2024	Observed in patients with breast or prostate cancer, co-occurring with a BRCA2 pathogenic variant in at least one individual (PMID: 28503720, 30287823, 30851065, 32832836, 33471991); Published functional studies suggest no damaging effect: DNA damage response and cell growth similar to wild type in a yeast-based assay (PMID: 30851065); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.1696C>T; p.(R566C); This variant is associated with the following publications: (PMID: 25980754, 30851065, 29866652, 30287823, 31398194, 32906215, 33471991, 28503720, Vazquez-Juarez2022[abstract], 32832836, 37031196, 24123366, 31874108, 35643632) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 23, 2023

Variant summary: CHEK2 c.1567C>T (p.Arg523Cys) 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 3.4e-05 in 233364 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1567C>T has been reported in the literature in individuals affected with breast cancer and other tumor phenotypes (Yurgelun_2015, Rummel_2017, Momozawa_2018, Vargas-Parra_2020, Dorling_2021), however the variant was also reported in controls (e.g. Dorling_2021 and in the FLOSSIES database). In addition, in one of the reported cases a co-occurrence with another pathogenic variant has been reported (BRCA2 c.7007G>A, p.Arg2336His; Rummel_2017), providing supporting evidence for a benign role. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating in a yeast based DNA-damage assay that the variant showed similar function to the wild type (Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30851065, 30287823, 28503720, 32906215, 25980754, 33471991). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, partly without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

CHEK2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2023

The CHEK2 c.1567C>T variant is predicted to result in the amino acid substitution p.Arg523Cys. This variant has been reported as uncertain significance in individuals with breast cancer, Lynch syndrome, or unspecified cancer (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Supplementary Data 1, Momozawa et al. 2018. PubMed ID: 30287823; Table S1, Vargas-Parra et al. 2020. PubMed ID: 32906215; Breast Cancer Association et al. 2021. PubMed ID: 33471991). This variant was also observed to co-occur with a pathogenic BRCA2 variant in an individual with breast cancer (Rummel et al. 2017. PubMed ID: 28503720). A yeast-based functional study showed that this variant does not affect protein function (Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.0086% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29083950-G-A) and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141007/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

May 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

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

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.077

LIST_S2

Uncertain

0.87

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

M_CAP

Benign

0.072

MetaRNN

Benign

0.13

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

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.0

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.1

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

REVEL

Benign

0.10

Sift

Benign

0.060

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

Sift4G

Benign

0.11

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

Polyphen

0.94

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

Vest4

0.11

MVP

0.78

MPC

0.080

ClinPred

0.17

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.060

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