NM_007194.4:c.920G>A

Variant summary

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

The NM_007194.4(CHEK2):​c.920G>A​(p.Gly307Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. G307R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

11
6
2

Clinical Significance

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

Conservation

PhyloP100: 6.67

Publications

3 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
MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHEK2NM_007194.4 linkc.920G>A p.Gly307Glu missense_variant Exon 9 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.920G>A p.Gly307Glu missense_variant Exon 9 of 15 1 NM_007194.4 ENSP00000385747.1 O96017-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461324
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726968
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33458
American (AMR)
AF:
0.00
AC:
0
AN:
44704
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86206
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000270
AC:
3
AN:
1111566
Other (OTH)
AF:
0.00
AC:
0
AN:
60378
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.542
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
31

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
Jan 04, 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. -

Oct 16, 2023
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 03, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 307 of the CHEK2 protein (p.Gly307Glu). This variant is not present in population databases (gnomAD no frequency). 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: 234497). 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. 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 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. -

Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Prostate cancer;C0585442:Bone osteosarcoma;C5882668:CHEK2-related cancer predisposition Uncertain:1
Apr 10, 2022
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Feb 29, 2016
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is denoted CHEK2 c.920G>A at the cDNA level, p.Gly307Glu (G307E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Gly307Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Gly307Glu occurs at a position that is conserved across species and is located in the protein kinase domain and an ATP binding region (Roeb 2012, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CHEK2 Gly307Glu is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1
Jun 14, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.G307E variant (also known as c.920G>A), located in coding exon 8 of the CHEK2 gene, results from a G to A substitution at nucleotide position 920. The glycine at codon 307 is replaced by glutamic acid, an amino acid with similar properties. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.38
T;.;T;.;T;.;T;.;.;.;.;.
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.91
.;D;.;D;.;D;D;D;.;D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Uncertain
2.8
M;M;M;.;M;.;M;.;M;.;.;.
PhyloP100
6.7
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-7.7
D;D;D;.;D;D;.;D;D;D;.;D
REVEL
Pathogenic
0.76
Sift
Pathogenic
0.0
D;D;D;.;D;D;.;D;D;D;.;D
Sift4G
Pathogenic
0.0
D;D;D;.;D;D;.;D;D;D;.;.
Polyphen
1.0
D;D;D;.;D;D;D;D;D;.;.;.
Vest4
0.93
MutPred
0.95
Loss of ubiquitination at K312 (P = 0.1139);Loss of ubiquitination at K312 (P = 0.1139);Loss of ubiquitination at K312 (P = 0.1139);.;Loss of ubiquitination at K312 (P = 0.1139);.;Loss of ubiquitination at K312 (P = 0.1139);.;Loss of ubiquitination at K312 (P = 0.1139);.;.;.;
MVP
0.98
MPC
0.17
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.84
Mutation Taster
=3/97
disease causing

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

Other links and lift over

dbSNP: rs876661053; hg19: chr22-29095914; API