ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1421G>A (p.Arg474His) (rs121908706)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000114766 SCV000149909 uncertain significance not provided 2018-06-06 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1421G>A at the cDNA level, p.Arg474His (R474H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant was observed in two individuals with triple negative breast cancer and in one individual with non Hodgkin lymphoma (Couch 2015, Havranek 2015). Although this variant was observed in large population cohorts, population data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). CHEK2 Arg474His is located in the kinase domain (Cai 2009, 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 Arg474His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000116000 SCV000172827 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-20 criteria provided, single submitter clinical testing Insufficient evidence;Structural Evidence
Invitae RCV000206096 SCV000259372 uncertain significance Familial cancer of breast 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 474 of the CHEK2 protein (p.Arg474His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121908706, ExAC 0.01%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 25452441, 30333958), and an individual with non-Hodgkin lymphoma (PMID: 26506619). This variant is also known as p.Arg517His in the literature. ClinVar contains an entry for this variant (Variation ID: 126910). 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: "Probably Damaging"; 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000114766 SCV000609072 likely pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Color RCV000116000 SCV000684591 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-09 criteria provided, single submitter clinical testing
Counsyl RCV000206096 SCV000785113 uncertain significance Familial cancer of breast 2017-04-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000114766 SCV000888106 uncertain significance not provided 2017-11-20 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000206096 SCV001251426 uncertain significance Familial cancer of breast 2019-10-23 criteria provided, single submitter clinical testing
Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague RCV000114766 SCV000148661 not provided not provided no assertion provided not provided

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