rs533475838
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_007194.4(CHEK2):c.1561C>T(p.Arg521Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000451 in 1,595,990 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000046 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
1
14
4
Clinical Significance
Conservation
PhyloP100: 4.62
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 -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.14416143).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.1561C>T | p.Arg521Trp | missense_variant | 15/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.1561C>T | p.Arg521Trp | missense_variant | 15/15 | 1 | NM_007194.4 | ENSP00000385747.1 |
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000515 AC: 12AN: 233214Hom.: 0 AF XY: 0.0000312 AC XY: 4AN XY: 128214
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GnomAD4 exome AF: 0.0000464 AC: 67AN: 1443690Hom.: 0 Cov.: 30 AF XY: 0.0000487 AC XY: 35AN XY: 718608
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GnomAD4 genome 0.0000328 AC: 5AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74464
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Uncertain:5
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 31, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 521 of the CHEK2 protein (p.Arg521Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27783279, 28580595, 30287823, 32068069, 34903604, 34991090). This variant is also known as c.1690C>T (p.Arg564Trp). ClinVar contains an entry for this variant (Variation ID: 140881). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 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 | 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 | Baylor Genetics | Feb 28, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 06, 2022 | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 30, 2022 | Variant summary: CHEK2 c.1561C>T (p.Arg521Trp) 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 309214 control chromosomes, predominantly at a frequency of 0.00044 within the East Asian subpopulation in the gnomAD database. This frequency is slightly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00044 vs 0.00031), suggesting this variant may be benign. c.1561C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One study combined 30 population-based and 14 family-based studies and showed that this variant is not associated with breast cancer (OR=2.48, p=0.0819). At least two publications report experimental evidence evaluating an impact on protein function and showed that this variant has no or intermediate effect on protein function (Delimitsou_2019, Boonen_2022). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 13, 2019 | - - |
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 16, 2024 | Published functional studies are inconclusive: DNA damage response comparable to wild type in a yeast-based assay, intermediate to impaired kinase activity, and aberrant protein localization (PMID: 30851065, 34903604, 37449874); 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; Also known as c.1690C>T, p.(Arg564Trp); Observed in individuals with breast and/or ovarian cancer, prostate cancer, or biliary tract cancers, but also in healthy controls (PMID: 30287823, 28580595, 27783279, 34991090, 34326862, 36243179, 35534704, 37842866); This variant is associated with the following publications: (PMID: 22090377, 27783279, 28580595, 30287823, 34426522, 34903604, 34991090, 32906215, 37449874, 36243179, 34326862, 30851065, 22419737, 33471991, 39146382, 35534704, 37842866, 39594831) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 18, 2019 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 08, 2023 | This missense variant replaces arginine with tryptophan at codon 521 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). Functional studies have shown this variant to be neutral in yeast-based DNA damage repair assay (PMID: 30851065) but to have an intermediate level of function in a mouse embryonic stem cell-based Kap1 phosphorylation assay (PMID: 34903604). This variant has been reported in individuals affected with breast, pancreatic, and colorectal cancer, but also in control individuals (PMID: 27783279, 28580595, 30287823, 32980694, 33309985, 33471991, 34991090, 37449874). This variant has been identified in 14/264616 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 | Apr 21, 2023 | The p.R521W variant (also known as c.1561C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1561. The arginine at codon 521 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been detected in breast cancer probands from Korea and Japan, but also has been seen in Japanese healthy control populations (Kim H et al. Breast Cancer Res. Treat. 2017 01;161(1):95-102; Momozowa Y et al. Nat Commun 2018 10;9(1):4083). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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 | Apr 26, 2023 | - - |
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.Arg521Trp variant was identified in 5 of 11648 proband chromosomes (frequency: 0.0004) from German and Korean individuals or families with breast cancer (including BRCA1/2-negative cases; Hauke 2018, Kim 2017). The variant was also identified in dbSNP (ID: rs533475838) as “With Likely benign, Uncertain significance allele” and ClinVar (classified uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Color and Quest Diagnostics Nichols Institute San Juan Capistrano). The variant was identified in control databases in 14 of 259842 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 22546 chromosomes (freq: 0.00004), European in 5 of 121862 chromosomes (freq: 0.00004), and East Asian in 8 of 18540 chromosomes (freq: 0.0004), while it was not observed in the Other, Latino, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Arg521 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. One computational study suggested that the variant could have resulted from an interlocus gene conversion event (Cassola 2012). 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
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D;.;D;.;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;.;D;.;D;D;D;.
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.;L;.;L;.;L;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;.;D;D;.;D;D
REVEL
Benign
Sift
Uncertain
D;D;D;.;D;D;.;D;D
Sift4G
Pathogenic
D;D;D;.;D;D;.;D;D
Polyphen
D;D;D;.;D;D;D;D;D
Vest4
MutPred
Gain of methylation at K520 (P = 0.0314);.;Gain of methylation at K520 (P = 0.0314);.;Gain of methylation at K520 (P = 0.0314);.;Gain of methylation at K520 (P = 0.0314);.;.;
MVP
MPC
0.053
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at