ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588723 SCV000149908 likely pathogenic not provided 2021-02-05 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25980754, 26506619, 22138346, 26094658, 19782031, 27900359, 29522266, 29520813, 28580595, 30426508, 29731985, 30851065, 30287823, 30858171, 31398194, 31159747)
Ambry Genetics RCV000115999 SCV000183823 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-04 criteria provided, single submitter clinical testing The p.R474C variant (also known as c.1420C>T), located in coding exon 12 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1420. The arginine at codon 474 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in the homozygous state in siblings with multiple primary lung cancers; the sister was also affected with breast cancer and uterine myoma and the brother was also affected with prostate and colon cancers (Kukita Y et al Cold Spring Harb. Mol. Case Stud. 2016 Nov;2(6):a001032). In addition, this alteration has been reported in the heterozygous state in multiple cohorts of affected patients with various tumor types (Wu Y et al. Prostate. 2018 Jun;78(8):607-615; Momozawa Y et al. Nat Commun, 2018 Oct;9:4083; Schubert S et al. Int. J. Cancer 2019 06;144(11):2683-2694; Xie Y et al. Clin. Genet. 2018 Jan;93(1):41-51; Tsaousis GN et al. BMC Cancer 2019 Jun;19(1):535). This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 05;40(5):631-648). The p.R474C variant has been shown to eliminate a salt bridge between the core kinase domain and the highly conserved activation loop, and is critical for stability and function of Ser/Thr kinases​ (Ambry internal analysis; Cai Z et al. Mol. Cell. 2009 Sep;35:818-29; Yang J et al. J. Mol. Biol. 2012 Jan;415:666-79). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000206044 SCV000261289 uncertain significance Familial cancer of breast 2020-10-18 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 individual(s) with breast cancer, prostate cancer, lung cancer, and/or Lynch syndrome-associated cancer(s) (PMID: 28580595, 30426508, 30287823, 29520813, 25980754, 27900359). This variant is also known as c.1549C>T (p.Arg517Cys) in the literature. ClinVar contains an entry for this variant (Variation ID: 128059). This variant has been reported to affect CHEK2 protein function (PMID: 30851065, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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)."
GeneKor MSA RCV000115999 SCV000821992 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588723 SCV000888105 uncertain significance not provided 2020-03-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764370 SCV000895405 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588723 SCV001153645 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115999 SCV001342781 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-28 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 474 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant is deficient in DNA damage response by yeast based DNA damage repair assays (PMID: 30851065) and UV damage-induced phosphorylation assays (PMID: 29522266). This variant has been reported in individuals affected with prostate cancer, breast cancer, thyroid cancer and Lynch-syndrome associated cancer (PMID: 25980754, 29520813, 29522266, 30269267, 30426508). This variant has been reported in an individual affected with pancreatic cancer, who also carried a pathogenic variant in the BRCA2 gene (PMID: 29731985). This variant has been identified in 4/233784 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000588723 SCV001715367 uncertain significance not provided 2020-04-30 criteria provided, single submitter clinical testing
Department of Molecular and Medical Genetics,Osaka Medical Center for Cancer and Cardiovascular Diseases RCV000234795 SCV000282240 likely pathogenic Familial cancer of breast; Lung carcinoma; 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.

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