rs747797219

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_007194.4(CHEK2):​c.1542G>T​(p.Gln514His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000209 in 1,438,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q514R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense, splice_region

Scores

5
14
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 4.57

Publications

5 publications found
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 Gene-Disease associations (from GenCC):
  • CHEK2-related cancer predisposition
    Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
  • hereditary breast carcinoma
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
  • Li-Fraumeni syndrome 2
    Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
  • acute myeloid leukemia
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • hereditary nonpolyposis colon cancer
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • familial ovarian cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHEK2NM_007194.4 linkc.1542G>T p.Gln514His missense_variant, splice_region_variant Exon 14 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.1542G>T p.Gln514His missense_variant, splice_region_variant Exon 14 of 15 1 NM_007194.4 ENSP00000385747.1 O96017-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000428
AC:
1
AN:
233512
AF XY:
0.00000780
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000921
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000209
AC:
3
AN:
1438494
Hom.:
0
Cov.:
29
AF XY:
0.00000140
AC XY:
1
AN XY:
716526
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33276
American (AMR)
AF:
0.00
AC:
0
AN:
44686
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26082
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39646
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86030
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
38008
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4122
European-Non Finnish (NFE)
AF:
0.00000181
AC:
2
AN:
1106724
Other (OTH)
AF:
0.0000167
AC:
1
AN:
59920
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.023284), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.392
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
ExAC
AF:
0.00000870
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:4
Dec 12, 2022
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 514 of the CHEK2 protein (p.Gln514His). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 4 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs747797219, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 410014). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in the activation of a cryptic splice site in exon 14 (Invitae). 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. -

Mar 16, 2018
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 08, 2023
Myriad Genetics, Inc.
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Hereditary cancer-predisposing syndrome Uncertain:2
Apr 11, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.Q514H variant (also known as c.1542G>T), located in coding exon 13 of the CHEK2 gene, results from a G to T substitution at nucleotide position 1542. The amino acid change results in glutamine to histidine at codon 514, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 13, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of 4 amino acids; however, the exact functional impact of the deleted amino acids is unknown at this time (Ambry internal data). The nucleotide and amino acid positions are highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Mar 16, 2020
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces glutamine with histidine at codon 514 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). This variant causes a G>T nucleotide substitution at the last nucleotide of exon 14 of the CHEK2 gene, and splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/233512 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 provided Uncertain:1
Oct 08, 2019
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Located at the last nucleotide of the exon and predicted to result in abnormal splicing leading to an in-frame deletion of exon 14; Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); While protein-based in silico analysis supports that this variant does not alter protein structure/function, splice predictors support a deleterious effect. However, in the absence of RNA or functional studies, the actual effect of this sequence change is unknown. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.038
T
BayesDel_noAF
Benign
-0.29
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
T;.;T;.;T;.;T;.;.
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.75
.;T;.;T;.;T;T;T;.
M_CAP
Uncertain
0.088
D
MetaRNN
Benign
0.33
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
0.97
L;.;L;.;L;.;L;.;.
PhyloP100
4.6
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.90
N;N;N;.;N;N;.;N;N
REVEL
Benign
0.11
Sift
Benign
0.39
T;T;T;.;T;T;.;D;T
Sift4G
Benign
0.13
T;T;T;.;T;T;.;T;T
Polyphen
0.97
D;D;D;.;D;D;D;D;D
Vest4
0.38
MutPred
0.18
Gain of catalytic residue at Q514 (P = 0.0536);.;Gain of catalytic residue at Q514 (P = 0.0536);.;Gain of catalytic residue at Q514 (P = 0.0536);.;Gain of catalytic residue at Q514 (P = 0.0536);.;.;
MVP
0.81
MPC
0.12
ClinPred
0.77
D
GERP RS
5.5
Varity_R
0.21
gMVP
0.31
Mutation Taster
=42/58
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.84
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.59
Position offset: 12
DS_DL_spliceai
0.84
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs747797219; hg19: chr22-29085123; API