rs587780179

Positions:

Variant summary

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

The NM_007194.4(CHEK2):c.1525C>T(p.Pro509Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,594,024 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P509P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:3O:1

Conservation

PhyloP100: 0.464

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=0.061661243).

BP6

Variant 22-28689152-G-A is Benign according to our data. Variant chr22-28689152-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128063.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, not_provided=1, Uncertain_significance=10}. Variant chr22-28689152-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1525C>T	p.Pro509Ser	missense_variant	14/15	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.1525C>T	p.Pro509Ser	missense_variant	14/15	1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151886

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000813

AC:

AN:

233628

Hom.:

AF XY:

0.0000779

AC XY:

AN XY:

128314

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000851

Gnomad NFE exome

AF:

0.000156

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000985

AC:

142

AN:

1442138

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

717936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000290

Gnomad4 NFE exome

AF:

0.000111

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000132

AC:

AN:

151886

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74154

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.000113

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:3Benign: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	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 509 of the CHEK2 protein (p.Pro509Ser). 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 breast cancer, colorectal cancer, Lynch syndrome, ovarian cancer, prostate cancer, skin cancer, and/or uterine cancer (PMID: 18571837, 25980754, 28051113, 29596542, 31050813). ClinVar contains an entry for this variant (Variation ID: 128063). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065, 31409080). 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	Counsyl	Apr 14, 2016	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2021	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: intermediate to normal activity with respect to DNA damage response and kinase activity (Delimitsou 2019, Kleiblova 2019); Observed in individuals with breast, ovarian, prostate, and other cancers (Tischkowitz 2008, Yurgelun 2015, Castellanos 2017, Kleiblova 2019); This variant is associated with the following publications: (PMID: 32906215, 27535533, 31050813, 31422574, 30851065, 29596542, 28420421, 28051113, 18571837, 25980754) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 05, 2024	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	Mar 03, 2016	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 01, 2024

Variant summary: CHEK2 c.1525C>T (p.Pro509Ser) 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 8.1e-05 in 233628 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (8.1e-05 vs 0.00031), allowing no conclusion about variant significance. c.1525C>T has been reported in the literature in individuals affected with breast cancer, prostate cancer, Lynch syndrome, and other cancers (e.g. Castellanos_2015, Lu_2016, Yurgelun_2015, Tischowitz_2008, Nunziato_2022, Vargas-Parra_2020, Boonen_2022), although it has also been reported in healthy individuals (e.g. Kraemer_2019, Boonen_2022, FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome or other CHEK2-related cancers. Several publications report experimental evidence evaluating an impact on protein function. A yeast-based DNA-damage assay indicated an intermediate functionality for the variant (Delimitsou_2019), whereas studies in Chek2 knockout mouse embryonic stem cells and in human RPE1-CHEK2-knockout cells found no damaging effect of the variant on its ability to phosphorylate its downstream target KAP1 (Boonen_2022, Stolarova_2023). The following publications have been ascertained in the context of this evaluation (PMID: 28051113, 30851065, 31422574, 27023146, 26644315, 18571837, 25980754, 37449874, 36035419, 32906215, 34903604). ClinVar contains an entry for this variant (Variation ID: 128063). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

CHEK2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2022

The CHEK2 c.1525C>T variant is predicted to result in the amino acid substitution p.Pro509Ser. This variant was reported in a patient with prostate cancer of Ashkenazi Jewish origin (Tischkowitz et al. 2008, PubMed ID: 18571837) and also in two individuals with suspected Lynch syndrome (Yurgelun et al. 2015, Supplemental Table 2, PubMed ID: 25980754). This variant is reported in 0.020% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29085140-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128063/?new_evidence=true). 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;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

- -

Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Malignant tumor of prostate

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 11-29-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.0

DANN

Benign

0.50

DEOGEN2

Benign

0.34

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

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.65

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

M_CAP

Benign

0.044

MetaRNN

Benign

0.062

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.7

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

REVEL

Benign

0.088

Sift

Benign

0.081

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

Sift4G

Benign

0.10

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

Polyphen

0.0

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

Vest4

0.17

MutPred

0.18

Gain of phosphorylation at P509 (P = 0.0378);.;Gain of phosphorylation at P509 (P = 0.0378);.;Gain of phosphorylation at P509 (P = 0.0378);.;Gain of phosphorylation at P509 (P = 0.0378);.;.;

MVP

0.30

MPC

0.020

ClinPred

0.032

GERP RS

-2.3

Varity_R

0.11

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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