ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.542G>A (p.Arg181His) (rs121908701)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129670 SCV000184468 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000129670 SCV000684656 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000233960 SCV000488568 uncertain significance Familial cancer of breast 2016-04-28 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765623 SCV000896948 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000114761 SCV000210965 uncertain significance not provided 2018-08-16 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.542G>A at the cDNA level, p.Arg181His (R181H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant, also published as CHEK2 Arg224His, has been observed in patients with neuroblastoma, lymphoma, breast cancer, and prostate cancer, and was absent among controls; however, the differences were not statistically significant (Dong 2003, Dufault 2004, Havranek 2011, Pugh 2013, Havranek 2015, Kaur 2018). CHEK2 Arg181His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the FHA domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 Arg181His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague RCV000114761 SCV000148656 not provided not provided no assertion provided not provided
Invitae RCV000233960 SCV000289689 uncertain significance Familial cancer of breast 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 181 of the CHEK2 protein (p.Arg181His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121908701, ExAC 0.1%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with prostate cancer, neuroblastoma, breast cancer, Hodgkin lymphoma, and non-Hodgkin lymphoma (PMID: 12533788, 23334666, 15095295, 21744992, 26506619). ClinVar contains an entry for this variant (Variation ID: 5598). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000233960 SCV000839486 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
OMIM RCV000005946 SCV000026128 pathogenic Prostate cancer, somatic 2003-02-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212428 SCV000601173 uncertain significance not specified 2017-02-07 criteria provided, single submitter clinical testing

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