22-28695786-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The ENST00000404276.6(CHEK2):​c.1183G>C​(p.Val395Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V395F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CHEK2
ENST00000404276.6 missense

Scores

3
10
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:12

Conservation

PhyloP100: 4.13
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 Uncertain_significance. Variant got 2 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in ENST00000404276.6

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CHEK2NM_007194.4 linkuse as main transcriptc.1183G>C p.Val395Leu missense_variant 11/15 ENST00000404276.6 NP_009125.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CHEK2ENST00000404276.6 linkuse as main transcriptc.1183G>C p.Val395Leu missense_variant 11/151 NM_007194.4 ENSP00000385747 P2O96017-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152210
Hom.:
0
Cov.:
32
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251068
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135724
show subpopulations
Gnomad AFR exome
AF:
0.0000616
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:
0.0000462
Gnomad NFE exome
AF:
0.0000441
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000205
AC:
30
AN:
1461616
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
AN XY:
727118
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
Gnomad4 NFE exome
AF:
0.0000261
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000588
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:4
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Mar 09, 2023This 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 submitterclinical testingBaylor GeneticsFeb 07, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylNov 02, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 395 of the CHEK2 protein (p.Val395Leu). This variant is present in population databases (rs587780170, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer and/or ovarian cancer (PMID: 28135145, 31050813). ClinVar contains an entry for this variant (Variation ID: 128049). 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. -
not specified Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalJul 31, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 11, 2023Variant summary: CHEK2 c.1183G>C (p.Val395Leu) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of 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 2.8e-05 in 251068 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1183G>C has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with breast and/or colorectal cancer (example, Yurgelun_2017, Kleibova_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (example, Delimitsou_2019). These results showed no damaging effect of this variant in ability of CHEK2 to repair MMS induced DNA damage in a yeast based cell system. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=8) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 10, 2022The CHEK2 c.1183G>C; p.Val395Leu variant (rs587780170) is reported in the literature in an individual with colorectal cancer (Yurgelun 2017) and an individual with ovarian cancer (Kleiblova 2019). This variant is also reported by multiple laboratories in the ClinVar database (Variation ID: 128049). One functional in vivo yeast-based assay showed the variant to be neutral (Delimitsou 2019). However, in vitro and cell-based kinase assays the variant was shown to be deleterious (Kleiblova 2019). This variant is found in the general population with an overall allele frequency of 0.003% (7/251068 alleles) in the Genome Aggregation Database. The valine at codon 395 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.478). Based on available information, the clinical significance of this variant is uncertain at this time. References: Delimitsou A et al. Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat. 2019 May;40(5):631-648. PMID: 30851065. Kleiblova P et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019 Oct 1;145(7):1782-1797. PMID: 31050813. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095. PMID: 28135145. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 06, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colon, ovarian, and other cancers, and also in unaffected controls (PMID: 28135145, 31050813); Published functional studies showed no impact on DNA damage response in yeast-based assays, while a human cell-based assay demonstrated defective kinase activity (PMID: 30851065, 31050813); This variant is associated with the following publications: (PMID: 28135145, 30851065, 31050813, 32295079, Ozair2021[Abstract], Dosunmu2021[Abstract], 34628056, 28779002, 19782031, 22419737) -
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 14, 2023The p.V395L variant (also known as c.1183G>C), located in coding exon 10 of the CHEK2 gene, results from a G to C substitution at nucleotide position 1183. The valine at codon 395 is replaced by leucine, an amino acid with highly similar properties. This alteration has been identified in both individuals with breast cancer and healthy controls (Decker B et al. J Med Genet, 2017 11;54:732-741). Functional analyses of this allele have produced conflicting results (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648; Kleiblova P et al. Int J Cancer, 2019 10;145:1782-1797). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 16, 2022This missense variant replaces valine with leucine at codon 395 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). Functional studies have shown this variant to have deleterious effect on CHEK2 function in in vitro and cell-based kinase assays but have neutral effect in yeast-based DNA damage repair assays (PMID 30851065, 31050813). In a large breast cancer case-control study, this variant has been observed in 11/60455 cases and 7/53454 controls (OR=1.389, 95%CI [0.539 to 3.585], p-value=0.638) (PMID: 33471991). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 7/251068 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. -
Breast and/or ovarian cancer Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingCZECANCA consortiumJun 11, 2019- -
CHEK2-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 14, 2024The CHEK2 c.1183G>C variant is predicted to result in the amino acid substitution p.Val395Leu. This variant was previously reported in individuals with cancer, including colorectal or ovarian cancer (see, for example, Yurgelun et al. 2017. PubMed ID: 28135145; Kleiblova et al. 2019. PubMed ID: 31050813, see supplementary table S3). However, in one breast cancer cohort study, this variant was present in both affected individuals and healthy controls (Dorling et al. 2021. PubMed ID: 33471991, supplementary data, reported as chr22_29091774_C_G). Additionally, a functional analysis of the p.Val395Leu variant protein in a yeast model indicated that this change may be benign (Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128049/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submittercurationGerman Consortium for Hereditary Breast and Ovarian Cancer, University Hospital CologneSep 09, 2024According to the ACMG SVI adaptation criteria we chose this criterion: PS3 (strong pathogenic): Stolarova 2023: damaging bei CHK2 und KAP-Assay; Kleiblova 2019: damaging bei KAP1- und Omnia Kinase Assay; Delimitsou 2019: benign -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.18
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.23
T;.;T;.;T;.;T;.;.
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
.;D;.;D;.;D;D;D;.
M_CAP
Benign
0.036
D
MetaRNN
Uncertain
0.60
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.41
T
MutationAssessor
Benign
1.0
L;.;L;.;L;.;L;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-2.3
N;N;N;.;N;N;.;N;N
REVEL
Uncertain
0.48
Sift
Uncertain
0.0090
D;D;D;.;D;D;.;D;D
Sift4G
Uncertain
0.014
D;D;D;.;D;D;.;D;D
Polyphen
0.97
D;D;D;.;D;P;D;D;D
Vest4
0.84
MVP
0.64
MPC
0.026
ClinPred
0.36
T
GERP RS
4.7
Varity_R
0.69
gMVP
0.76

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: rs587780170; hg19: chr22-29091774; COSMIC: COSV60428575; COSMIC: COSV60428575; API