ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.538C>T (p.Arg180Cys)

gnomAD frequency: 0.00051  dbSNP: rs77130927
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 22
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588124 SCV000149933 likely benign not provided 2020-10-21 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Case-control studies are inconclusive regarding association with breast cancer (Southy 2016, Decker 2017); Observed in individuals with breast, prostate, or ovarian cancer (Dong 2003, Dufault 2004, Kleibl 2008, Mohelnikova-Duchonova 2010, Le Calvez-Kelm 2011, Liu 2011, Mohamad 2015, Ng 2016, Chirasophon 2017, Xie 2017); Also known as CHEK2 c.667C>T (p.Arg223Cys); Published functional studies are inconclusive: intermediate response to DNA damage (Walsh 2011, Roeb 2012); This variant is associated with the following publications: (PMID: 26757417, 26483394, 28580595, 18085035, 30826992, 31060593, 25629968, 12533788, 22995991, 25980754, 25525159, 15095295, 20643596, 21618645, 24549055, 21244692, 27153395, 27498913, 22419737, 27595995, 21744992, 18058223, 18996005, 27621404, 23960188, 27783279, 22006311, 23555315, 28188963, 28452373, 28779002, 19782031, 29879026, 29470806, 30287823, 30851065, 31050813, 31422574, 29667044, 29263802, 32566746, 32041497, 33326660, 32906215)
Ambry Genetics RCV000116024 SCV000185905 benign Hereditary cancer-predisposing syndrome 2016-07-26 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Intact protein function observed in appropriate functional assay(s);No disease association in appropriately sized case-control study(ies);Subpopulation frequency in support of benign classification
Invitae RCV000196561 SCV000253487 benign Familial cancer of breast 2021-12-17 criteria provided, single submitter clinical testing
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490304 SCV000267255 uncertain significance Malignant tumor of prostate 2016-03-18 criteria provided, single submitter reference population
Counsyl RCV000196561 SCV000488845 uncertain significance Familial cancer of breast 2016-07-06 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000212426 SCV000594118 uncertain significance not specified 2016-07-18 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000116024 SCV000689694 benign Hereditary cancer-predisposing syndrome 2016-02-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588124 SCV000698810 likely benign not provided 2016-08-08 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.538C>T (p.Arg180Cys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 168/123378 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0040472 (35/8648). This frequency is about 142 times the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant has been reported in numerous affected individuals in the literature including breast and prostate cancer patients, however no co-segregation and limited co-occurrence data is provided by these studies. In addition, the variant is also reported in unaffected controls in these studies, suggesting the variant is not causitive in these populations. In a yeast-based functional assay, the variant had an intermediate response to DNA damage (Roeb_2012). Multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS while one has classified it as likely benign. Taken together, this variant is classified as likely benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000116024 SCV000747819 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-16 criteria provided, single submitter clinical testing
Mendelics RCV000196561 SCV000839487 benign Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588124 SCV000889337 uncertain significance not provided 2021-05-11 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030689 SCV001193565 uncertain significance Hereditary breast ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Illumina Laboratory Services,Illumina RCV001149530 SCV001310488 uncertain significance CHEK2-Related Cancer Susceptibility 2017-04-27 criteria provided, single submitter clinical testing 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000196561 SCV001368127 uncertain significance Familial cancer of breast 2019-07-08 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP6.
Molecular Oncology Research Center,Barretos Cancer Hospital RCV001030689 SCV001438608 likely pathogenic Hereditary breast ovarian cancer syndrome 2020-08-01 criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000588124 SCV001471442 likely benign not provided 2022-01-13 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000196561 SCV002009490 uncertain significance Familial cancer of breast 2021-11-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798358 SCV002043408 uncertain significance Breast and/or ovarian cancer 2019-12-03 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV001030689 SCV002505166 uncertain significance Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000116024 SCV002537611 likely benign Hereditary cancer-predisposing syndrome 2021-06-09 criteria provided, single submitter curation
Genetics and Molecular Pathology, SA Pathology RCV000196561 SCV002556371 uncertain significance Familial cancer of breast 2020-10-07 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000588124 SCV001549905 uncertain significance not provided no assertion criteria provided clinical testing The CHEK2 p.Arg180Cys variant was identified in 172 of 93852 proband chromosomes (frequency: 0.002) from individuals or families with hereditary breast and ovarian cancer, prostate cancer and Lynch syndrome and was present in 147 of 89446 control chromosomes (frequency: 0.002) from healthy individuals (Dong 2003, Dufault 2004, Kleibl 2008, Laitman 2007, Mohamad 2015, Mohelnikova Duchonova 2010, Ng 2016, Southey 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs77130927) as “With other allele”, ClinVar (classified as benign by Color Genomics, Ambry Genetics, and Mendelics Analise Genomica; as likely benign by Invitae and Integrated Genetics; and as uncertain significance by GeneDx, Counsyl, and 4 other submitters). The variant was identified in control databases in 261 of 277166 chromosomes at a frequency of 0.0009, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 14 of 24018 chromosomes (freq: 0.0006), Other in 6 of 6468 chromosomes (freq: 0.0009), Latino in 2 of 34420 chromosomes (freq: 0.00006), European (Non-Finnish) in 153 of 126674 chromosomes (freq: 0.001), Ashkenazi Jewish in 2 of 10152 chromosomes (freq: 0.0002), East Asian in 58 of 18866 chromosomes (freq: 0.003), European (Finnish) in 5 of 25788 chromosomes (freq: 0.0002), and South Asian in 21 of 30780 chromosomes (freq: 0.0007). In a functional yeast assay, the response of the p.Arg180Cys CHEK2 variant to DNA damage was found to be decreased to 0.64 of wild type (1.00; Roeb 2012). A large study of the Breast Cancer Association Consortium found an association with breast cancer risk to be 1.33 odds ratio (Southey 2016). The p.Arg180 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.