22-28725004-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_007194.4(CHEK2):āc.565A>Gā(p.Ile189Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000034 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 2.93
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251418Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135898
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461838Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727224
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74298
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 31, 2023 | This missense variant replaces isoleucine with valine at codon 189 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Two yeast-based DNA damage response assays have shown different results for the impact of this variant on protein function. One showed the variant to be non-functional (PMID: 22419737) and the other showed functional (PMID: 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 22419737, 28495237), colon cancer (PMID: 22419737), soft tissue sarcoma (PMID: 26556299), and ovarian cancer (PMID: 28591191). This variant has also been identified in 1/251418 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2023 | The p.I189V variant (also known as c.565A>G), located in coding exon 3 of the CHEK2 gene, results from an A to G substitution at nucleotide position 565. The isoleucine at codon 189 is replaced by valine, an amino acid with highly similar properties. This alteration is located in the FHA domain and was characterized as damaging based on a yeast-based assay to assess in vivo CHEK2-mediated response to DNA damage (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). However, this alteration behaved as functional in a different in vivo yeast-based growth assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This alteration was detected in two patients who underwent multi-gene panel testing, both of whom had early-onset breast cancer and a family history of colon cancer (Frey MK et al. Gynecol Oncol. 2017 May 8). It has also been identified in an individual with soft tissue sarcoma who also carried a germline BRCA2 mutation (Schrader K et al. JAMA Oncol 2016 Jan;2(1):104-11). 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. - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 12, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 189 of the CHEK2 protein (p.Ile189Val). This variant is present in population databases (rs587780185, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer and ovarian cancer and soft tissue sarcoma and breast and colon cancer (PMID: 22419737, 26556299, 28495237, 28591191). This variant is also known as I232V. ClinVar contains an entry for this variant (Variation ID: 128082). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 22419737, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 05, 2023 | - - |
not provided Uncertain:1Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Uncertain significance and reported on 03-09-2020 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 11, 2023 | Not 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 breast, ovarian, and other cancers, and did not show loss of heterozygosity in a sarcoma sample (Schrader et al., 2016; Frey et al., 2017; Stafford et al., 2017); Published functional studies are conflicting with respect to DNA damage response activity (Roeb et al., 2012; Delimitsou et al., 2019); This variant is associated with the following publications: (PMID: 26681312, 26556299, 28495237, 22419737, 28301460, 30851065, 28591191, 19782031) - |
Familial cancer of breast;C0346629:Colorectal cancer;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 | Jan 11, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;T;T;.;T;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T;.;.;T;T;.;T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;L;.;L;L;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;.;N;N;.
REVEL
Uncertain
Sift
Benign
D;D;D;D;D;.;D;D;.
Sift4G
Uncertain
D;T;D;D;T;.;T;T;D
Polyphen
D;P;D;D;D;D;P;.;.
Vest4
MutPred
Gain of disorder (P = 0.1246);Gain of disorder (P = 0.1246);Gain of disorder (P = 0.1246);Gain of disorder (P = 0.1246);.;Gain of disorder (P = 0.1246);Gain of disorder (P = 0.1246);.;Gain of disorder (P = 0.1246);
MVP
MPC
0.093
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at