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22 28695868 AG A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_007194.4(CHEK2):c.1100del(p.Thr367MetfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 152,324 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T367T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0022 ( 5 hom. )
Failed GnomAD Quality Control

Consequence

CHEK2
NM_007194.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:72U:1O:2

Conservation

PhyloP100: 8.67
Variant links:
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 Pathogenic. Variant got 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 22-28695868-AG-A is Pathogenic according to our data. Variant chr22-28695868-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 128042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695868-AG-A is described in Lovd as [Pathogenic]. Variant chr22-28695868-AG-A is described in Lovd as [Likely_pathogenic]. Variant chr22-28695868-AG-A is described in Lovd as [Likely_benign]. Variant chr22-28695868-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CHEK2NM_007194.4 linkuse as main transcriptc.1100del p.Thr367MetfsTer15 frameshift_variant 11/15 ENST00000404276.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CHEK2ENST00000404276.6 linkuse as main transcriptc.1100del p.Thr367MetfsTer15 frameshift_variant 11/151 NM_007194.4 P2O96017-1

Frequencies

GnomAD3 genomes
AF:
0.00172
AC:
262
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000265
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00202
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00904
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00216
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00204
AC:
509
AN:
248982
Hom.:
0
AF XY:
0.00203
AC XY:
274
AN XY:
135164
show subpopulations
Gnomad AFR exome
AF:
0.000395
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00160
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00873
Gnomad NFE exome
AF:
0.00254
Gnomad OTH exome
AF:
0.00165
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00220
AC:
3205
AN:
1459022
Hom.:
5
Cov.:
30
AF XY:
0.00213
AC XY:
1548
AN XY:
726030
show subpopulations
Gnomad4 AFR exome
AF:
0.000150
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00138
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00848
Gnomad4 NFE exome
AF:
0.00236
Gnomad4 OTH exome
AF:
0.00148
GnomAD4 genome
AF:
0.00172
AC:
262
AN:
152324
Hom.:
0
Cov.:
32
AF XY:
0.00195
AC XY:
145
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.000265
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00202
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00904
Gnomad4 NFE
AF:
0.00216
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000595
Hom.:
1
Bravo
AF:
0.00100
EpiCase
AF:
0.00185
EpiControl
AF:
0.00130

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:72Uncertain:1Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:18Other:1
Pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalFeb 06, 2024- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 23, 2023The CHEK2 c.1100delC; p.Thr367MetfsTer15 variant (rs555607708) is a well-studied variant that was originally associated with Li-Fraumeni syndrome (Bell 1999) and has since been reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 128042). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, in vitro functional analyses demonstrate a loss of CHEK2 kinase activity, supportive of a pathogenic effect (Lee 2001). This variant is also described as a founder variant in Northern European populations (Cybulski 2004), and is found in the Finnish European population with an allele frequency of 0.87% (219/25124 alleles) in the Genome Aggregation Database. This reduced penetrance variant is associated with an increased breast cancer risk (Bak 2014, Cybulski 2004, Cybulski 2007), and the overall lifetime breast cancer risk for CHEK2 pathogenic variants in general is 20-30% (Slavin 2015). This variant has also been associated with an increased risk of prostate cancer (Naslund-Koch 2016, Pritchard 2016, Wu 2018). There may be additional cancer risks associated with this variant but evidence is incomplete at this time. Based on available information, the c.1100delC variant is considered to be pathogenic. REFERENCES Bak A et al. A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland. Hered Cancer Clin Pract. 2014 12(1): 10. Bell DW et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999 286(5449):2528-31. Cybulski C et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004 75(6):1131-5. Cybulski C et al. A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. Breast Cancer Res Treat. 2007 102(1):119-22. Lee SB et al. Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res. 2001 61(22):8062-7. Naslund-Koch C et al. Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study. J Clin Oncol. 2016 Apr 10;34(11):1208-16. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Slavin TP et al. Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. Front Oncol. 2015 5:208. Wu Y et al. A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. Prostate. 2018 Jun;78(8):607-615. -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 04, 2022PP5, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsOct 11, 2021- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJul 21, 2020The CHEK2 c.1100del (p.Thr367Metfs*15) variant (also known as c.1100delC) alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer and other cancers (PMIDs: 31993860 (2020), 29522266 (2018), 28874143 (2017), 28779002 (2017), 26884562 (2016), 27223485 (2016), 15122511 (2004), 15087378 (2004), 11719428 (2001)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024CHEK2: PVS1, PP1:Strong, PS4:Moderate -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant interpretted as Pathogenic and reported most recently on 12-09-2019 by Lab or GTR ID 505849. The variant was also interpretted as pathogenic ad reported on 03-04-2017 by GTR ID 26957. 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. -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalJun 04, 2019- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 04, 2020Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of kinase activity (Lee 2001, Wu 2001); Case control studies suggest this variant is associated with several types of cancer, including breast, colon, prostate, gastric, renal, and thyroid (Seppala 2003, The CHEK2 Breast Cancer Consortium 2004, Cybulski 2006, Desrichard 2011, Teodorczyk 2013, Hale 2014, Ma 2014, Siolek 2015, Naslund-Koch 2016, Schmidt 2016, Couch 2017, Decker 2017, Katona 2017, Carlo 2018); This variant is associated with the following publications: (PMID: 11967536, 14648718, 18759107, 27269948, 14612911, 15122511, 17085682, 22114986, 23296741, 25431674, 23946381, 25583358, 26884562, 28418444, 28779002, 28734145, 29978187, 11719428, 11053450, 31948886, 32832836, 31980526, 32854451, 31263571, 32081490, 31447099, 32255556, 15818573, 32285038, 30777372, 31871297, 30957677, 31206626, 28514723, 31263054, 30877237, 31360903, 30612635, 30303537, 30676620, 30113427, 31159747, 30833417, 31090900, 30309722, 30322717, 29767408, 30623166, 29520813, 29445900, 30947698, 30426508, 29506128, 15095295, 30333958, 28135145, 29909963, 28727877, 25186627, 26556299, 28503720, 28802053, 27806230, 27798748, 28195393, 29489754, 28125075, 19768534, 29351919, 28944238, 29146883, 26332814, 29909568, 28874143, 25980754, 26681312, 22527104, 27083775, 26822237, 27153395, 26084796, 26641009, 27716369, 27488870, 21956126, 27751358, 28008555, 27433846, 27443514, 17661168, 16452051, 15087378, 21807500, 12690581, 14648719, 10617473, 15239132, 22006311, 23409019, 22058428, 23109706, 21876083, 22058216, 20722467, 23415889, 22811390, 19030985, 22520019, 21244692, 22691310, 22994785, 15492928, 23329222, 25835597, 24723567) -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 27, 2020- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Familial cancer of breast Pathogenic:14
Pathogenic, no assertion criteria providedclinical testingPathway GenomicsJul 24, 2014- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This sequence change creates a premature translational stop signal (p.Thr367Metfs*15) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is present in population databases (rs555607708, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This particular variant has been well described in the literature. In a large meta-analysis comprising 16 studies including 26,488 affected individuals and 27,402 controls, women heterozygous for this variant have a relative risk for familial breast cancer of 4.8 (95% CI, 3.3-7.2). The cumulative risk at age 70 years is 37% (95% CI, 26%-56%), compared to 7.8% for the average Caucasian woman in the general population (PMID: 18172190). Although one study has reported that the c.1100del variant confers an approximate 10-fold increased risk of male breast cancer (PMID: 11967536), the results have yet to be confirmed in further studies (PMID: 14648717, 14648718, 14648719, 15488637). ClinVar contains an entry for this variant (Variation ID: 128042). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingMendelicsJul 02, 2018- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterAug 24, 2022- -
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyDec 13, 2019- -
Pathogenic, criteria provided, single submitterresearchCentre for Mendelian Genomics, University Medical Centre LjubljanaDec 09, 2022PVS1, PS3, PS4_STR, BS1 -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterAug 14, 2023Criteria applied: PVS1,PS3,PS4,PM1 -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Mar 09, 2023This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria providedclinical testingBRCAlab, Lund UniversityAug 26, 2022- -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterNov 01, 2021PVS1, PS4, PS3 -
Pathogenic, criteria provided, single submitterclinical testingCounsylJan 20, 2016- -
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinOct 29, 2022ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJul 17, 2019This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 10617473, 23329222, 23415889, 22058428, 26332814, 24723567, 29146883] -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Molecular Diagnostics, Institute of Oncology LjubljanaApr 02, 2020- -
Hereditary cancer-predisposing syndrome Pathogenic:10
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 27, 2022The c.1100delC (p.T367Mfs*15) alteration, located in exon 11 (coding exon 10) of the CHEK2 gene, consists of a deletion of one nucleotide at position 1100, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Clinic-based studies have estimated an approximately 2-fold increase in female breast cancer, colorectal cancer, and melanoma risk associated with this alteration (CHEK2 Breast Cancer Case-Control, 2004; Xiang, 2011; Weischer, 2012). However, a recent population-based study found a 2-fold increase in female breast cancer risk and 6-fold increase in stomach cancer risk associated with this alteration, but did not find a statistically significant association with colon cancer or melanoma (Näslund-Koch, 2016). Another study found that risk for estrogen receptor (ER) positive breast cancer was more pronounced than risk for ER-negative breast cancer and estimated that the cumulative risks for development of ER-positive and ER-negative tumors by age 80 in carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom (Schmidt, 2016). This alteration has also been reported in male breast cancer cohorts (Leedom, 2016; Hallamies, 2017), and was identified in 5/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard, 2016). This alteration is located within the kinase domain, and is reported to abolish the kinase activity of CHK2 (Wu, 2001). Based on the available evidence, this alteration is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGeneKor MSAJan 01, 2020This variation is a deletion of 1 nucleotide from exon 11 of the CHEK2 mRNA (c.1100delC), causing a frameshift at codon 367. This creates a premature translational stop signal 15 amino acid residues later (p.Thr367Metfs*15) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic. This variant has been well described in the literature (PMID: 18172190). The mutation database ClinVar contains an entry for this variant (Variation ID: 128042). -
Pathogenic, no assertion criteria providedclinical testingTrue Health DiagnosticsNov 14, 2017- -
Pathogenic, no assertion criteria providedclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.Sep 27, 2021- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityJun 14, 2019- -
Pathogenic, criteria provided, single submitterresearchHauer Lab, Department Of Pediatric Oncology, Technical University Munich-ACMG/AMP, PVS1, PM2, PP5 -
Pathogenic, criteria provided, single submittercurationSema4, Sema4Oct 04, 2021- -
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 11, 2023This variant deletes 1 nucleotide in exon 11 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A large meta-analysis of breast cancer case-control studies has determined that female carriers of this variant show a relative risk for familial breast cancer of 4.8 (95% CI: [3.3, 7.2]) and cumulative risk at age 70 years of 37% (95% CI: [26, 56]) vs. 7.8% for the population controls (PMID: 18172190). Another meta-analysis has also shown a significant breast cancer risk in heterozygous carriers of this variant (OR=2.75, 95% CI: [2.25, 3.36]) (PMID: 22994785). The ORs and CIs were 2.33 (95% CI: [1.79, 3.05]), 3.72 (95% CI: [2.61, 5.31]) and 2.78 (95% CI: [2.28, 3.39]), respectively, in unselected, family, early-onset breast cancer subgroups in this study. This variant has been observed in individuals affected with colorectal cancer, but whether this variant is associated with increased risk of colorectal cancer remains uncertain (PMID: 21807500, 28135145, 28734145). This variant is well documented as a breast cancer-associated variant in the literature and in the public database (ClinVar variation ID: 128042). This variant has been identified in 591/280390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submittercase-controlCancer Variant Interpretation Group UK, Institute of Cancer Research, LondonApr 08, 2022Data included in classification: Deletion resulting in frameshift (PVS1_vstr) The CHEK2 Breast Cancer Consortium (https://doi.org/10.1038/ng879). 1.1% in healthy individuals/5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003) (PS4_str) Data not included in classification: Weischer et al 2008 (https://doi.org/10.1200/jco.2007.12.5922) OR 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer, OR is above 2 with lower CI ≥1.5. Wu et al., 2001 (PMID: 11053450), assay reports loss of kinase activity in functional studies. -
Pathogenic, criteria provided, single submitterresearchAcademic Department of Medical Genetics, University of CambridgeJan 26, 2018Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -
Li-Fraumeni syndrome 2 Pathogenic:3
Pathogenic, no assertion criteria providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasNov 24, 2023- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Immunology and Genetics KaiserslauternApr 24, 2024ACMG Criteria: PVS1, PS3, PS4, PP4, PP5 Variant was found in heterozygous state -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 16, 2024Criteria applied: PVS1,PS3,PS4 -
Colorectal cancer Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJun 09, 2023Criteria applied: PVS1,PS3,PS4,PM2_SUP -
Pathogenic, criteria provided, single submitterclinical testingHuman Genetics Bochum, Ruhr University BochumJul 01, 2022ACMG criteria used to clasify this variant: PVS1, PS3, PS4 -
Pathogenic, criteria provided, single submitternot providedInstitute of Human Genetics, University Hospital of Duesseldorf-- -
CHEK2-related cancer predisposition Pathogenic:2Other:1
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 9/2/2020 by Invitae, 2/22/2016 by Ambry Genetics, 12/16/2016 by Myriad, 3/4/2017 by GeneDx, and 9/11/17 by Myriad Women's Health. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 10, 2015The c.1100delC (p.Thr367fs) variant in CHEK2 has been associated with increased risk for several types of cancer, including breast, colorectal, and prostate. Me ta-analyses have reported an odds ratio of 2-4 for developing breast, colorectal , or prostate cancer, and a possibly smaller increased risk of malignant melanom a (Weischer 2008, Xiang 2011, Weischer 2012, Yang 2012, Wang 2015). In addition, animal models in mice have shown that this variant causes increased tumor forma tion in multiple cancer sites (Bahassi 2009). This variant has also been reporte d by other clinical laboratories in ClinVar (Variation ID 128042). Of note, this variant has been identified in 0.3% (319/125272) of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 35705950). Therefore, this variant is not expected to cause highly penetrant Men delian disease. In summary, the c.1100delC (p.Thr367fs) variant is an establishe d risk factor for breast, colorectal, and prostate cancers. -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017The CHEK2 c.1100delC (p.Thr367MetfsTer15) variant is a common variant in individuals of European origin and has been investigated in multiple studies in various cancer types. A meta-analysis of ten case-control studies, including 10,860 breast cancer cases and 9,065 controls by the CHEK2 Breast Cancer Case-Control Consortium (2004) found a statistically significant association between carrying the p.Thr367MetfsTer15 variant and increase in risk of breast cancer (OR=2.34). The association of the p.Thr367MetfsTer15 variant and increased risk of breast cancer was also supported by Bernstein et al. (2006) (OR=6.65) and Weischer et al. (2007) (OR=3.2). Weischer et al. (2007) also found an association between the variant and increased risk of prostate cancer (OR=2.3) and colorectal cancer (OR=1.6). Weischer et al. (2012) found an association of the p.Thr367MetfsTer15 variant and increased risk of malignant melanoma in both a case-control study (OR=1.79) and a meta-analysis (OR=1.81). The p.Thr367MetfsTer15 variant has also been identified in patients with Li-Fraumeni syndrome (Bell et al. 1999), colon, kidney, prostate, and thyroid cancers (Cybulski et al. 2004), ovarian cancer (Walsh et al. 2011), and uterine cancer (Pennington et al. 2013), though the associated risks for these cancers due to this variant are unclear at this time. Studies by Lee et al. (2001) found a lack of kinase activity and evidence of loss of heterozygosity in a tumor sample from a patient carrying the germline p.Thr367MetfsTer15 variant. The highest allele frequency reported in the 1000 Genomes database is 0.0202 in the Finnish population. Although an association with the p.Thr367MetfsTer15 variant and susceptibility to different cancers is widely reported, the increase in risk is low to moderate. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Breast and/or ovarian cancer Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingCZECANCA consortiumJun 11, 2019- -
Pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioMay 07, 2021- -
Breast and colorectal cancer, susceptibility to Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingUniversity of Washington Department of Laboratory Medicine, University of WashingtonNov 20, 2015- -
Pathogenic, criteria provided, single submitterclinical testingRady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego-This variant is also referred to as c.1100delC (p.Thr367MetfsTer15) (NM_007194.3) in the literature. This deletion in exon 12 of 16 causes a frameshift and a premature stop codon at residue 424 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). The c.1229del (p.Thr410MetfsTer15) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.2% (585/275092) and is present in the homozygous state at a frequency of 0.0004% (1/275092). This variant is enriched in the European (Finnish) population (MAF=0.87%). Based on two large case-control studies, the relative risk for female breast cancer associated with the c.1229del variant was 3.0 (90% CI, 2.6-3.5) (PMID: 26014596, 15122511, 23109706). Additionally, a meta-analysis reported a relative risk of 1.88 (95% C.I. 1.29-2.73) for colorectal cancer associated with the c.1229del variant (PMID: 23946381). The c.1229del variant has also been associated with an increased risk of prostate cancer (PMID: 26629066) and other cancers (PMID: 26884562, 21956126). Based on the available evidence, the c.1229del (p.Thr410MetfsTer15) variant is classified as Pathogenic. -
Carcinoma of pancreas Pathogenic:1
Pathogenic, no assertion criteria providedcase-controlCZECANCA consortiumMar 04, 2021- -
Leiomyosarcoma;C1458155:Breast neoplasm Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingGenome Sciences Centre, British Columbia Cancer Agency-Positive family history of early breast cancer (niece diagnosed at age 35). Whole genome sequencing (blood and tumor) and whole transcriptome sequencing (tumor) also revealed the germline CHEK2:c.1100delC pathogenic variant, which is considered a moderate penetrance allele for breast cancer. -
Breast neoplasm Pathogenic:1
Pathogenic, criteria provided, single submitterresearchA.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center-- -
TUMOR PREDISPOSITION SYNDROME 4, BREAST/PROSTATE/COLORECTAL Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 2006- -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateApr 19, 2022- -
Breast carcinoma Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingMedical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health SciencesAug 19, 2021Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive -
Li-Fraumeni syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterOct 26, 2023Criteria applied: PVS1,PS3,PS4 -
Breast cancer, susceptibility to Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoNov 22, 2021DNA sequence analysis of the CHEK2 gene demonstrated a single base pair deletion in exon 11, c.1100del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 15 amino acids downstream of the sequence change, p.Thr367Metfs*15. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CHEK2 protein with potentially abnormal function. In vitro functional studies have demonstrated that CHEK2 c.1100del change results in loss of kinase activity and the inability to phosphorylate Cdc25C, supportive of a pathogenic effect (PMIDs: 11719428, 11053450). This pathogenic sequence change is a well-known founder pathogenic variant with relative frequency in European populations. It is associated with an increased risk for cancer and has been described in multiple patients with CHEK2-related cancers, including breast cancer, lung cancer, thyroid cancer, gastric cancer, renal cancer, lymphoma and in individuals with possible Li-Fraumeni syndrome (PMID: 21956126, 23296741, 26884562, PMID: 26506619). -
Colitis;C0018932:Hematochezia;C0040034:Thrombocytopenia;C0578878:Inflammation of the large intestine Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Personalized Medicine, Children's Hospital Los Angeles-- -
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The CHEK2 p.Thr367Metfs*15 variant was identified in 1290 of 102960 proband chromosomes (frequency: 0.013) from individuals or families with breast, prostate, and colorectal cancer and was present in 1222 of 292928 control chromosomes (frequency: 0.004) from healthy individuals (Adank 2011, Cybulski 2004, Cybulski 2006, Dong 2003, Easton 2004, Ruijs 2009, Silva 2014, Weischer 2008, Xiang 2011, Yang 2012). The variant was also identified in the following databases: dbSNP (ID: rs555607708) as "With Pathogenic allele", ClinVar (12x, pathogenic), Clinvitae (6x, pathogenic), Cosmic (1x, salivary gland tumour sample), and the Zhejiang Colon Cancer Database (48x). The variant was not identified in the MutDB database. The variant was identified in control databases in 585 of 275092 chromosomes at a frequency of 0.002 (Genome Aggregation Consortium Feb 27, 2017). Of note, it was identified in the Finnish population in 221 of 25794 chromosomes (freq. 0.009) and in the European population in 319 of 125272 chromosomes (freq. 0.003). The c.1100delC variant is an established breast cancer susceptibility allele and is associated with a two- to three-fold increased risk for breast cancer at a median age of 53 years (Naslund-Koch 2016). This variant is also associated with an increased risk of additional cancer types, including prostate, colon, and others (Cybulski 2004, Xiang 2011). Functional studies involving wild-type and mutant CHEK2 proteins expressed in insect cells showed that the p.Thr367Metfs*15 protein lacks kinase activity, supportive of a pathogenic effect (Wu 2001). The c.1100delC variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 367 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Malignant tumor of prostate Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterMar 15, 2024Criteria applied: PVS1,PS3,PS4_MOD -
Predisposition to cancer Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalMay 24, 2022The CHEK2 c.1100del (p.Thr367MetfsTer15) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has been widely reported to be associated with cancer susceptibility, including significant associations with increased risk of breast cancer in large meta-analysis studies (odds ratios ~2-5, PMID: 18172190, 22994785). This variant has also been reported in individuals with colon, prostate, gastric, kidney, and thyroid cancer (PMID: 14612911, 15087378, 15492928, 16880452, 21807500, 23296741, 25431674, 25583358, 26884562). This change has an overall frequency of 0.21% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) and has been described as a founder variant in Northern European populations (PMID: 15087378). In summary, this variant meets criteria to be classified as pathogenic with evidence indicating lower penetrance. -
Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Malignant tumor of prostate Pathogenic:1
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologySep 26, 2022PVS1, PS4, PS3_Supporting -
Li-Fraumeni syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 25, 2019Variant summary: CHEK2 c.1100delC (p.Thr367MetfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.002 in 248982 control chromosomes (gnomAD). Although this variant was found at a relatively high frequency in controls, this is a well-known founder mutation that is known to be relatively frequent in European populations. c.1100delC has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and also as risk factor for several cancer types (breast, ovarian, prostate, colon, etc.). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this variant leads to loss of damage response and kinase activity (Lee_2001, Roeb_2012). Eighteen other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
CHEK2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 01, 2024The CHEK2 c.1100delC variant is predicted to result in a frameshift and premature protein termination (p.Thr367Metfs*15). This variant has been reported to be causative for hereditary breast cancer and uterine serous carcinoma (Bell et al. 1999. PubMed ID: 10617473; Pennington et al. 2013. PubMed ID: 22811390). In a large Danish study, this variant was associated with a statistically-significant increased risk of breast cancer (hazard ratio [HR]: 2.08, 95% CI: 1.51-2.85) and stomach cancer (HR: 5.76, 95%CI: 2.12-15.6; Näslund-Koch et al. 2016. PubMed ID: 26884562). In another study consisting of more than 80,000 breast cancer patients and age-appropriate controls, this variant was reported to have a higher risk for estrogen receptor-positive breast cancer (Schmidt et al. 2016. PubMed ID: 27269948). In addition, this variant has been associated with prostate (Hale et al. 2014. PubMed ID: 25431674) and colorectal cancers (Wasielewski et al. 2008. PubMed ID: 18676774; Xiang et al. 2011. PubMed ID: 21807500). Functional studies have shown that the c.1100del variant impairs CHEK2 activity (Lee et al. 2001. PubMed ID: 11719428; Roeb et al. 2012. PubMed ID: 22419737). This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128042/). Loss-of-function variants in CHEK2 are known to be pathogenic. This variant is interpreted as pathogenic. -
Bone osteosarcoma Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingClinical Genetics Laboratory, University Hospital Schleswig-HolsteinJul 26, 2021- -
Familial cancer of breast;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C1836482:Li-Fraumeni syndrome 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 18, 2017- -
Neoplasm of ovary Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDiagnostics Centre, Carl Von Ossietzky University OldenburgJul 28, 2023The variant CHEK2:c.1100delC, p.(Thr367fs), which is located in the coding exon 11 of the CHEK2 gene, results from a deletion of a nucleotide at position 1100. The variant causes a frameshift that results on the replace of threonine residue at protein position 367 by methionine and a premature stop codon follows after further 15 amino acids. The premature stop codon is predicted to cause protein truncation/absent and nonsense mediated decay in a gene where loss-of-function is a mechanism of disease. Multiple studies has shown that the variant is statistically significant associated to increased risk of breast and other type of cancer, including ovarian cancer (PMID: 16492927; 23109706; 21956126; 16880452; 28727877; 37055167). In one study, tumours were also detected statistically significantly more frequently in mice with the CHEK2 c.1100delC variant as compared to wild-type controls (PMID: 19805189). This variant is a known founder variant in the overall population and occurs with an allele frequency of < 1 % in gnomAD. The variant is classified as Pathogenic. -
Astrocytoma Uncertain:1
Uncertain significance, flagged submissionclinical testingLaboratory of Molecular Neuropathology, The University of Texas Health Science Center at Houston-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
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Prediction

Splicing

Name
Calibrated prediction
Score
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SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs555607708; hg19: chr22-29091856; COSMIC: COSV60419771; COSMIC: COSV60419771; API