ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000116007 SCV000186581 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000198277 SCV000254931 uncertain significance Familial cancer of breast 2019-12-30 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 been observed in an individual affected with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 128066). This variant has been reported to have conflicting or insufficient data to determine the effect on CHEK2 protein 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.
Counsyl RCV000198277 SCV000488450 uncertain significance Familial cancer of breast 2016-04-01 criteria provided, single submitter clinical testing
Color RCV000116007 SCV000537516 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-13 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
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
Integrated Genetics/Laboratory Corporation of America RCV000212476 SCV000698786 uncertain significance not specified 2019-01-07 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1556G>T (p.Arg519Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 261956 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Breast Cancer (0.00021 vs 0.00031), allowing no conclusion about variant significance. c.1556G>T has been reported in the literature in individuals affected with Breast Cancer (Singh_2018, Young_2016) . These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneKor MSA RCV000116007 SCV000821994 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
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 RCV000586195 SCV000889324 uncertain significance not provided 2018-10-11 criteria provided, single submitter clinical testing

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