ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1420C>T (p.Arg474Cys) (rs540635787)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115999 SCV000183823 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Department of Molecular and Medical Genetics,Osaka Medical Center for Cancer and Cardiovascular Diseases RCV000234795 SCV000282240 likely pathogenic Familial cancer of breast; Lung cancer; Malignant tumor of prostate; Carcinoma of colon no assertion criteria provided research Two siblings, an elder sister and a younger brother, were found to have multiple primary lung cancers at the age of 60. The former subsequently developed breast cancer, and had a history of myoma uteri. The latter had initially developed prostate cancer at the age of 59, and had a history of colon cancer. This variant was homozygous in both patients.
Fulgent Genetics,Fulgent Genetics RCV000764370 SCV000895405 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 RCV000588723 SCV000149908 uncertain significance not provided 2018-09-27 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1420C>T at the cDNA level, p.Arg474Cys (R474C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been observed in an individual with a Lynch-syndrome associated cancer and/or polyps, another with a personal and family history of prostate cancer, and at least two others with breast cancer (Yurgelun 2015, Wu 2018, Hauke 2018). This variant was also reported in the homozygous state in siblings with multiple adult-onset primary cancers (Kukita 2016). Functional studies by Kukita et al. (2016) demonstrated decreased CHEK2 protein expression and phosphorylation. 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). This variant 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 Arg474Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000115999 SCV000821992 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588723 SCV000698776 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.1420C>T (p.Arg474Cys) variant located in the protein kinase-like domain (InterPro) causes a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 1/113468, which does not exceed the estimated maximal expected allele frequency for a pathogenic CHEK2 variant of 1/35211. The variant of interest has been reported in a Lynch syndrome patient via a publication. Multiple reputable databases cite the variant with conflicting classifications "uncertain significance" or "likely pathogenic." Therefore, until additional clinical and/or functional studies become available, the variant of interest has been classified as a "Variant of Uncertain Significane (VUS)."
Invitae RCV000206044 SCV000261289 uncertain significance Familial cancer of breast 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 474 of the CHEK2 protein (p.Arg474Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs540635787, ExAC 0.01%). This variant has been observed in individuals affected with suspected Lynch syndrome or prostate cancer (PMID: 25980754, 29520813). ClinVar contains an entry for this variant (Variation ID: 128059). Experimental studies have shown that this missense change causes the protein to be unstable and poorly activated by DNA damage in vitro (PMID: 27900359). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588723 SCV000888105 likely pathogenic not provided 2018-03-22 criteria provided, single submitter clinical testing

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