rs587782527
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6
The NM_007194.4(CHEK2):c.1216C>T(p.Arg406Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000638 in 1,613,698 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R406H) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000061 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
8
11
Clinical Significance
Conservation
PhyloP100: 3.63
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=0.40644896).
BP6
Variant 22-28695753-G-A is Benign according to our data. Variant chr22-28695753-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142533.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=13}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.1216C>T | p.Arg406Cys | missense_variant | 11/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.1216C>T | p.Arg406Cys | missense_variant | 11/15 | 1 | NM_007194.4 | ENSP00000385747 | P2 |
Frequencies
GnomAD3 genomes 0.0000920 AC: 14AN: 152142Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000518 AC: 13AN: 250830Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135672
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GnomAD4 exome AF: 0.0000609 AC: 89AN: 1461438Hom.: 0 Cov.: 31 AF XY: 0.0000646 AC XY: 47AN XY: 727062
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GnomAD4 genome 0.0000919 AC: 14AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74460
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:15Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:6
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 16, 2023 | Published functional studies demonstrate no damaging effect: similar growth rates to the wild-type in a yeast-based assay (Delimitsou et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history of sarcoma, breast, ovarian, or other cancers (Osorio et al., 2004; Le Calvez-Kelm et al., 2011; Rashid et al., 2013; Ballinger et al., 2016; Girard et al., 2019; Guindalini et al., 2022); Also known as c.1345C>T (p.Arg449Cys); This variant is associated with the following publications: (PMID: 26787654, 23741719, 28514183, 28553140, 25629968, 23806170, 14618615, 27498913, 21244692, 29173497, 28102005, 29368341, 29596542, 30303537, 32322110, 19782031, 22419737, 35495172, 30851065, 35264596) - |
| Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 01, 2023 | In the published literature, this variant has been reported in individuals and families with breast/ovarian cancer (PMIDs: 35402282 (2022), 35264596 (2022), 32885271 (2021), 30303537 (2019), 30441849 (2018), 23806170 (2013), 21244692 (2011), 14618615 (2004)), and prostate cancer (PMID: 29368341 (2018)). It has also been observed in breast cancer cases and unaffected control individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). In addition, an experimental study reports this variant has a neutral effect on CHEK2 protein function in yeast (PMID: 30851065 (2019)). The frequency of this variant in the general population, 0.00014 (5/35430 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 01, 2020 | The CHEK2 c.1216C>T; p.Arg406Cys variant (rs587782527) is reported in the literature in individuals with breast, ovarian, or prostate cancer (Isaacsson 2018, Le Calvez-Kelm 2011, Osorio 2004, Rashid 2013), and is reported in ClinVar (Variation ID: 142533). This variant is found in the general population with an overall allele frequency of 0.006% (17/282232 alleles) in the Genome Aggregation Database. The arginine at codon 406 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Additionally, an in vivo yeast-based functional assay suggests that this variant is benign (Delimitsou 2019). However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Delimitsou A et al. Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat. 2019 May;40(5):631-648. Isaacsson Velho P et al. Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer. Prostate. 2018 Apr;78(5):401-407. Le Calvez-Kelm F et al. Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res. 2011 Jan 18;13(1):R6. Osorio A et al. The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population. Int J Cancer. 2004 Jan 1;108(1):54-6. Rashid MU et al. Constitutional CHEK2 mutations are infrequent in early-onset and familial breast/ovarian cancer patients from Pakistan. BMC Cancer. 2013 Jun 27;13:312. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Sep 23, 2022 | - - |
Familial cancer of breast Uncertain:3Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 08, 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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 406 of the CHEK2 protein (p.Arg406Cys). This variant is present in population databases (rs587782527, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, hepatoblastoma, and/or ovarian cancer (PMID: 14618615, 21244692, 23806170, 29368341, 35495172). ClinVar contains an entry for this variant (Variation ID: 142533). 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 | Mendelics | Jul 02, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 21, 2016 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 25, 2023 | This missense variant replaces arginine with cysteine at codon 406 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). A functional study has reported this variant protein as benign in a yeast complementation assay (PMID: 30851065). This variant has been reported in individuals with personal and/or family history of breast and ovarian cancer (PMID: 14618615, 21244692, 23806170, 30441849, 30303537, 32885271, 35402282), prostate cancer (PMID: 29368341), and sarcoma (PMID: 27498913). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 9/60466 cases and 9/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000187). This variant has also been identified in 17/282232 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 | Feb 08, 2023 | The p.R406C variant (also known as c.1216C>T), located in coding exon 10 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1216. The arginine at codon 406 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified in numerous disease cohorts (Osorio A et al. Int. J. Cancer. 2004 Jan;108:54-6; Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6; Rashid MU et al. BMC Cancer. 2013 Jun;13:312; Ballinger ML et al. Lancet Oncol. 2016 Sep;17:1261-71; Young EL et al. J Med Genet, 2016 06;53:366-76; Decker B et al. J Med Genet, 2017 11;54:732-741; Isaacsson Velho P et al. Prostate. 2018 Apr;78:401-407; Koczkowska M et al. Cancers (Basel), 2018 Nov;10:; Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). 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). This amino acid position is well conserved in available vertebrate species. 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. - |
CHEK2-related disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 14, 2023 | The CHEK2 c.1216C>T variant is predicted to result in the amino acid substitution p.Arg406Cys. This variant has been reported in individuals with breast cancer (Osorio et al. 2004. PubMed ID: 14618615; Table S1 - Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Table S3, Girard et al. 2018. PubMed ID: 30303537; Table S3, Guindalini et al. 2022. PubMed ID: 35264596), an individual with ovarian cancer (Rashid et al. 2013. PubMed ID: 23806170; Table S1, Koczkowska et al. 2018. PubMed ID: 30441849), an individual with prostate cancer (Table S1 - Isaacsson Velho et al. 2018. PubMed ID: 29368341), and an individual with hepatoblastoma (Aguiar et al. 2022. PubMed ID: 35495172). Functional studies found this variant does not differ significantly from wild type CHEK2 (Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29091741-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142533/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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 | Jul 05, 2022 | - - |
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 | - - |
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.Arg406Cys variant was identified in 1 of 290 proband chromosomes (frequency: 0.003) from Pakistani individuals or families with BRCA1/2 negative early-onset and familial breast/ovarian cancers and was not identified in 300 control chromosomes from healthy individuals, or 229 individuals with BRCA1/2 negative breast/ovarian cancers (Rashid 2013). In a yeast complementation assay assessing protein function of the Arg406His variant, the variant did not abrogate CHEK2 function, with yeast cells carrying the Arg406His variant growing at a similar rate to those carrying wildtype (Yilmaz 2014). The variant was also identified in in dbSNP (ID: rs587782527) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry genetics, GeneDx, Invitae, and Counsyl), Clinvitae; and in control databases in 17 of 276708 chromosomes at a frequency of 0.00006 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The p.Arg406 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Cys 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, 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. - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 22, 2024 | Variant summary: CHEK2 c.1216C>T (p.Arg406Cys) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 1,610,078 control chromosomes (gnomAD v4 dataset). This frequency is not higher than the estimated maximum 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. The variant, c.1216C>T, has been reported in the literature in individuals affected with personal and/or family history of breast-, ovarian-, and prostate cancer (e.g. Calvez-Kelm_2011, Rashid_2013, Osorio_2004, Isaacsson_2018, Koczkowska_2018, Girard_2019, Dorling_2021, Guindalini_2022). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 9/60466 cases, but was also found in 9/53461 controls (Dorling_2021, reported through LOVD). Co-occurrences with other pathogenic variants have been reported (BRCA1 c.1326T>A, p.Cys442X and BRCA2 c.6468_6469delTC, p.Q2157fs*18; in internal LCA samples), providing supporting evidence for a benign role. In a yeast functional study, the variant was found to be benign (Delimitsou_2019). ClinVar contains an entry for this variant (Variation ID: 142533). Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.;T;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;.;D;.;D;D;D;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L;.;L;.;L;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;.;D;D;.;D;D
REVEL
Benign
Sift
Benign
T;T;T;.;T;D;.;D;T
Sift4G
Benign
T;T;T;.;T;T;.;D;T
Polyphen
P;D;P;.;P;P;P;D;D
Vest4
MutPred
Gain of catalytic residue at V408 (P = 0.0684);.;Gain of catalytic residue at V408 (P = 0.0684);.;Gain of catalytic residue at V408 (P = 0.0684);.;Gain of catalytic residue at V408 (P = 0.0684);.;.;
MVP
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0.038
ClinPred
D
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gMVP
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at