22-28725013-T-G
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6
The ENST00000404276.6(CHEK2):c.556A>C(p.Asn186His) variant causes a missense change. The variant allele was found at a frequency of 0.000144 in 1,613,946 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N186D) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
CHEK2
ENST00000404276.6 missense
ENST00000404276.6 missense
Scores
4
12
3
Clinical Significance
Conservation
PhyloP100: 5.73
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.756
BP6
Variant 22-28725013-T-G is Benign according to our data. Variant chr22-28725013-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141977.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=11}. Variant chr22-28725013-T-G is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.556A>C | p.Asn186His | missense_variant | 4/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.556A>C | p.Asn186His | missense_variant | 4/15 | 1 | NM_007194.4 | ENSP00000385747 | P2 |
Frequencies
GnomAD3 genomes 0.0000920 AC: 14AN: 152100Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251420Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135898
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GnomAD4 exome AF: 0.000150 AC: 219AN: 1461846Hom.: 0 Cov.: 32 AF XY: 0.000140 AC XY: 102AN XY: 727220
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GnomAD4 genome 0.0000920 AC: 14AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74300
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:19Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:9Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 18, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2023 | Identified in individuals with breast and other cancers as well as in controls, and segregation was incomplete in one breast cancer family (Tung et al., 2015; Decker et al., 2017; Girard et al., 2019; Hilbers et al., 2020; Song et al., 2021); Published functional studies suggest no damaging effect: no impact on kinase activity in a mouse ES cell-based system and growth rates similar to wild type following DNA damage in a yeast-based assay (Delimitsou et al., 2019; Boonen et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26094658, 30303537, 28873162, 28825729, 28779002, 32383162, 30374176, 32546565, 30851065, 25186627, 34903604, 19782031, 22419737) - |
| Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | CHEK2: BS3:Supporting - |
| Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Familial cancer of breast Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 09, 2023 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 186 of the CHEK2 protein (p.Asn186His). This variant is present in population databases (rs146198085, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer and/or pleomorphic xanthoastrocytoma and meningioma (PMID: 26094658, 30303537, 30374176, 32383162, 34903604). This variant is also known as c.685T>G (p.Asn229His). ClinVar contains an entry for this variant (Variation ID: 141977). 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 have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065, 34903604). 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 | Counsyl | Sep 01, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 27, 2022 | _x000D_ Criteria applied: PM2_SUP, PP3 - |
not specified Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2022 | Variant summary: CHEK2 c.556A>C (p.Asn186His) results in a conservative amino acid change located in the Forkhead-associated (FHA) domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251420 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (6e-05 vs 0.00031), allowing no conclusion about variant significance. c.556A>C has been reported in the literature in individuals affected with Breast Cancer (example Aloraifi_2015, Tung_2015, Girard_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. It has also been reported among women older than age 70 years who have never had cancer in the FLOSSIES database. At-least two co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.2359dupG, p.Glu787GlyfsX3 (Tung_2015); BRCA1 c.130T>A, p.Cys44Ser, at our laboratory), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Delimitsou_2019). These results showed no damaging effect of this variant in an in-vivo, yeast based, functional assay. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=7, likely benign, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant retained its classification as likely benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 30, 2020 | This alteration is classified as likely 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 09, 2023 | This missense variant replaces asparagine with histidine at codon 186 of the CHEK2 protein. this variant is also known as p.Asn229His in the literature based on an alternate transcript NM_001005735. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to exhibit normal CHEK2 protein expression and function (PMID: 30851065, 34903604). This variant has been reported in two individuals affected with breast cancer (PMID: 25186627, 26094658). In a large breast cancer case-control study, this variant has been observed in 27/60439 individuals affected with breast cancer and 15/53446 controls (OR=1.592, 95%CI 0.847 to 2.993; PMID: 33471991). This variant has been identified in 19/282804 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. - |
CHEK2-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 03, 2024 | The CHEK2 c.556A>C variant is predicted to result in the amino acid substitution p.Asn186His. This variant has been reported in individuals with breast cancer and an individual undergoing genetic testing (Supplement, Tung et al. 2015. PubMed ID: 25186627; Table S1, referred to as c.685T>G, p.Asn229His, Aloraifi et al. 2015. PubMed ID: 26094658; Table S3, Girard et al. 2018. PubMed ID: 30303537; Table S1, Tsai et al. 2018. PubMed ID: 30374176). In vivo experimental investigation using a yeast based assay suggest this variant is benign (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as uncertain significance by the vast majority of submitters to ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/141977/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Familial cancer of breast;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 | May 23, 2017 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Endometrial carcinoma Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHEK2 p.Asn186His variant was identified in 1 of 208 proband chromosomes (frequency: 0.005) from individuals or families with non-BRCA1/2 breast cancer and was not identified in 202 control chromosomes from healthy individuals (Aloraifi 2015). The variant was identified in dbSNP (ID: rs146198085) as “With Uncertain significance allele”, in ClinVar (classified with conflicting interpretations of pathogenicity: likely benign by Laboratory Corporation of America; and uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Fulgent Genetics and Color Genomics Inc), Clinvitae (4x), Cosmic (1x in a wilms tumour), and Zhejiang Colon Cancer Database (1x), but was not found in MutDB. The variant was also identified in control databases in 18 of 277188 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 3 of 24028 chromosomes (freq: 0.0001), and European Non-Finnish in 15 of 126684 chromosomes (freq: 0.0001); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Asn186 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant His to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D;D;.;D;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;.;.;D;D;.;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;.;M;M;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;.;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;.;D;D;.
Sift4G
Uncertain
D;D;D;D;D;.;D;D;D
Polyphen
D;D;D;D;D;D;D;.;.
Vest4
MVP
MPC
0.16
ClinPred
D
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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