ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1556G>T (p.Arg519Leu) (rs587780180)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116007 SCV000186581 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000116007 SCV000537516 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
Counsyl RCV000198277 SCV000488450 uncertain significance Familial cancer of breast 2016-04-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515321 SCV000611454 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000586195 SCV000149916 uncertain significance not provided 2018-04-04 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1556G>T at the cDNA level, p.Arg519Leu (R519L) at the protein level, and results in the change of an Arginine to a Leucine (CGA>CTA). CHEK2 Arg519Leu was not observed among 1,313 early-onset breast cancer cases but was identified in 1/1,123 controls (Le Calvez-Kelm 2011). This variant was not observed in large population cohorts (Lek 2016). CHEK2 Arg519Leu is located in the NLS domain (Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Arg519Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000116007 SCV000821994 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212476 SCV000594112 uncertain significance not specified 2017-01-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586195 SCV000698786 uncertain significance not provided 2015-11-13 criteria provided, single submitter clinical testing
Invitae RCV000198277 SCV000254931 uncertain significance Familial cancer of breast 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 519 of the CHEK2 protein (p.Arg519Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs587780180, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 128066). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Mendelics RCV000198277 SCV000839452 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212476 SCV000601157 uncertain significance not specified 2016-12-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586195 SCV000889324 uncertain significance not provided 2017-11-07 criteria provided, single submitter clinical testing

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.