rs17883862

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_001257387.2(CHEK2):​c.-524C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000546 in 1,613,706 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 31)
Exomes 𝑓: 0.00037 ( 3 hom. )

Consequence

CHEK2
NM_001257387.2 5_prime_UTR_premature_start_codon_gain

Scores

3
16

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:23O:1

Conservation

PhyloP100: 0.336
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.004856348).
BP6
Variant 22-28734468-G-A is Benign according to our data. Variant chr22-28734468-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 5594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734468-G-A is described in Lovd as [Benign]. Variant chr22-28734468-G-A is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHEK2NM_007194.4 linkc.254C>T p.Pro85Leu missense_variant Exon 2 of 15 ENST00000404276.6 NP_009125.1 O96017-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHEK2ENST00000404276.6 linkc.254C>T p.Pro85Leu missense_variant Exon 2 of 15 1 NM_007194.4 ENSP00000385747.1 O96017-1

Frequencies

GnomAD3 genomes
AF:
0.00226
AC:
344
AN:
152090
Hom.:
1
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00681
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00302
Gnomad ASJ
AF:
0.00231
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000915
AC:
230
AN:
251444
Hom.:
1
AF XY:
0.000684
AC XY:
93
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.00843
Gnomad AMR exome
AF:
0.000954
Gnomad ASJ exome
AF:
0.00387
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000158
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000366
AC:
535
AN:
1461498
Hom.:
3
Cov.:
33
AF XY:
0.000337
AC XY:
245
AN XY:
727072
show subpopulations
Gnomad4 AFR exome
AF:
0.00753
Gnomad4 AMR exome
AF:
0.000895
Gnomad4 ASJ exome
AF:
0.00414
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000639
Gnomad4 OTH exome
AF:
0.000977
GnomAD4 genome
AF:
0.00227
AC:
346
AN:
152208
Hom.:
1
Cov.:
31
AF XY:
0.00220
AC XY:
164
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.00684
Gnomad4 AMR
AF:
0.00301
Gnomad4 ASJ
AF:
0.00231
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000980
Hom.:
0
Bravo
AF:
0.00270
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00704
AC:
31
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000882
AC:
107
EpiCase
AF:
0.000164
EpiControl
AF:
0.000474

ClinVar

Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Benign:23Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6Other:1
Aug 06, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 09, 2017
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 27, 2013
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

not provided Benign:6
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 17, 2020
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 01, 2017
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 09, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The CHEK2 c.254C>T (p.Pro85Leu) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 143/130972 control chromosomes (1 homozygote) including ExAC, predominantly observed in the African subpopulation at a frequency of 0.007411 (77/10390). This frequency is about 24 times the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant has been reported in multiple breast cancer patients without clear evidence supporting causality. Although one functional study showed in vitro kinase actitiy of CHEK2 p.P85L was 40-50% of wild-type CHEK2, two additional functional studies showed this variant does not affect yeast growth rate or in vivo response to DNA damage. In addition, multiple clinical laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:4
Aug 24, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Jun 20, 2016
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

Dec 08, 2014
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 14, 2017
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial cancer of breast Benign:4
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 25, 2016
Counsyl
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 09, 2023
Myriad Genetics, Inc.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Bone osteosarcoma Pathogenic:1
Jan 01, 2002
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Breast and/or ovarian cancer Benign:1
May 02, 2022
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The CHEK2 p.Pro85Leu variant was identified in 31 of 5508 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer and was present in 31 of 6844 control chromosomes (frequency: 0.005) from healthy individuals (Bell 2007, Shaag 2005, Le Calvez-Kelm 2011, Bodian 2014). The variant was also identified in dbSNP (ID: rs17883862 as With Pathogenic, Uncertain significance allele), ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Quest Diagnostics Nichols Institute San Juan Capistrano, and Color Genomics and as likely benign by Counsyl and four other clinical laboratories) and the Zhejiang University Database (as neutral allele). The variant was not identified in Cosmic or MutDB. The variant was identified in control databases in 285 of 277140 chromosomes (1 homozygous) at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). This variant was observed in the following populations: African in 192 of 24018 chromosomes (freq: 0.008), Ashkenazi Jewish in 39 of 10152 chromosomes (freq: 0.004), Latino in 33 of 34416 chromosomes (freq: 0.001), Other in 1 of 6460 chromosomes (freq: 0.0002), European in 18 of 126662 chromosomes (freq: 0.0001), and South Asian in 2 of 30780 chromosomes (freq: 0.0001), but not in the East Asian or Finnish populations. The p.Pro85 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing. Several in vitro studies show DNA damage response by this variant is consistent with that of the wild-type protein (Nevanlinna 2006, Shaag 2005, Roeb 2012). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Hereditary breast ovarian cancer syndrome Benign:1
Apr 19, 2022
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.11
T;.;T;T;.;T;.;.;.;.;T;.;T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.75
D
LIST_S2
Uncertain
0.89
.;D;.;.;D;D;D;.;D;D;D;D;D
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.0049
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.030
D
MutationAssessor
Benign
1.7
L;L;L;L;L;L;L;L;.;.;.;.;.
PrimateAI
Benign
0.43
T
PROVEAN
Benign
0.10
N;N;N;N;N;.;N;N;N;N;D;.;D
REVEL
Benign
0.10
Sift
Benign
0.13
T;T;T;T;D;.;D;T;D;D;D;.;D
Sift4G
Benign
0.19
T;T;T;T;T;.;D;T;T;T;D;.;.
Polyphen
0.73
P;P;P;P;D;P;D;P;.;.;.;.;.
Vest4
0.32
MVP
0.96
MPC
0.021
ClinPred
0.017
T
GERP RS
1.1
Varity_R
0.031
gMVP
0.26

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.

Other links and lift over

dbSNP: rs17883862; hg19: chr22-29130456; COSMIC: COSV60422781; COSMIC: COSV60422781; API