rs199708878
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_001257387.2(CHEK2):c.-771C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,612,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
CHEK2
NM_001257387.2 5_prime_UTR_premature_start_codon_gain
NM_001257387.2 5_prime_UTR_premature_start_codon_gain
Scores
1
10
8
Clinical Significance
Conservation
PhyloP100: 2.88
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 Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.01741594).
BP6
Variant 22-28734715-G-A is Benign according to our data. Variant chr22-28734715-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142209.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=6, Benign=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.7C>T | p.Arg3Trp | missense_variant | 2/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.7C>T | p.Arg3Trp | missense_variant | 2/15 | 1 | NM_007194.4 | ENSP00000385747.1 |
Frequencies
GnomAD3 genomes 0.000139 AC: 21AN: 151442Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000278 AC: 68AN: 244816Hom.: 1 AF XY: 0.000249 AC XY: 33AN XY: 132754
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GnomAD4 exome AF: 0.000135 AC: 198AN: 1461358Hom.: 0 Cov.: 33 AF XY: 0.000154 AC XY: 112AN XY: 726934
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GnomAD4 genome 0.000139 AC: 21AN: 151560Hom.: 0 Cov.: 31 AF XY: 0.000176 AC XY: 13AN XY: 73998
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 09, 2020 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 20, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 16, 2021 | 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 | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jan 24, 2023 | - - |
Familial cancer of breast Uncertain:1Benign:2
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 09, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 15, 2016 | - - |
not specified Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 29, 2024 | Variant summary: CHEK2 c.7C>T (p.Arg3Trp) results in a non-conservative amino acid change in 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 0.00028 in 251936 control chromosomes, predominantly at a frequency of 0.00036 within the Ashkenazi Jewish and South Asian subpopulations in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.15 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031). c.7C>T has been reported in the literature in individuals affected with Breast and Ovarian Cancer as well as LFS, prostate cancer, and diffuse large B cell lymphoma without strong evidence for causality/neutral outcome (example, Lee_2001, Laitman_2007, Bell_2007, Tischowitz_2008, deMiranda_2013, Tung_2014, Rummel_2017, Kleiblova_2019). In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 7/60466 cases, but was also found in 3/53461 controls (Dorling_2021, reported through LOVD). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Multiple publications reported experimental evidence evaluating an impact on protein function, and one study showed that the variant resulted in a mildly reduced response to DNA damage (Roeb_2012), while several other studies indicated that the variant demonstrated kinase activity and growth in yeast comparable to wild-type (Lee_2001, Kleiblova_2019, Delimitsou_2019, Stolarova_2023). A recent large-scale meta-analysis reported the variant in 9/73048 breast cancer cases and 7/88658 controls (Stolarova_2023), and concluded (also considering the results of the in vitro functional studies) that the variant was not associated with statistically significantly increased risk for breast cancer. The following publications have been ascertained in the context of this evaluation (PMID: 17721994, 30851065, 31050813, 18085035, 11719428, 22419737, 28503720, 18571837, 25186627, 23960188, 33471991, 37449874). ClinVar contains an entry for this variant (Variation ID: 142209). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 30, 2024 | Observed in individuals with CHEK2-related and other cancers, but also observed in unaffected controls (PMID: 11719428, 17721994, 18085035, 18571837, 28503720); Published functional studies demonstrate no damaging effect: most show no or minimal impact on DNA damage response/kinase activity (PMID: 11719428, 17721994, 22419737, 30851065, 31050813); 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: 17721994, 22419737, 14569133, 19338683, 23960188, 12610780, 27273131, 31398194, 16080966, 11719428, 18085035, 18571837, 28211887, 28503720, 28873162, 25186627, 24482476, 26296696, 28553140, 30851065, 31050813, 36845387, 33939675) - |
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 08, 2023 | - - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 18, 2020 | - - |
CHEK2-related cancer predisposition Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHEK2 p.Arg3Trp variant was identified in 7 of 6118 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer, prostate cancer, Li-Fraumeni Syndrome or diffuse large B-cell lymphomas and was identified in 2 of 7128 control chromosomes from healthy individuals (Bell 2007, Laitman 2007, Lee 2001, Miranda 2013, Rummel 2017, Schutte 2003, Tischkowitz 2008). The variant was also identified in dbSNP (ID: rs199708878 as "With Uncertain significance allele"), ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Color Genomics, and Integrated Genetics/Laboratory Corporation of America), and the Zhejiang University Database (4x). The variant was not identified in MutDB database. The variant was identified in control databases in 71 of 270350 chromosomes (1 homozygous) at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 2 of 6344 chromosomes (freq: 0.0003), Latino in 1 of 34306 chromosomes (freq: 0.00003), European in 7 of 120922 chromosomes (freq: 0.0001), Ashkenazi Jewish in 48 of 9970 chromosomes (freq: 0.01), East Asian in 2 of 18812 chromosomes (freq: 0.0001), and South Asian in 11 of 30678 chromosomes (freq: 0.0004), while the variant was not observed in the African, and Finnish populations. The p.Arg3 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact 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. The variant showed intermediate DNA damage response in CHEK2-mediated DNA damage response assay (Roeb 2012). However, the variant did not show LOH in a primary tumor specimen and demonstrated kinase activity and protein half-life comparable with that of the wild-type protein; the primary tumor assayed was also found to have a homozygous somatic variant in TP53 (Lee 2001). 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. - |
Hereditary cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Sep 11, 2024 | This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T;T;.;T;.;.;.;.;T;.;T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;.;.;D;D;D;.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;L;L;L;L;L;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;.;N;N;N;N;D;.;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;.;D;D;D;D;D;.;D
Sift4G
Uncertain
D;D;D;D;D;.;D;D;D;D;D;.;.
Polyphen
D;D;D;D;D;D;D;D;.;.;.;.;.
Vest4
MVP
MPC
0.083
ClinPred
T
GERP RS
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gMVP
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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