ClinVar Miner

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

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Total submissions: 16
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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 The p.R519L variant (also known as c.1556G>T), located in coding exon 14 of the CHEK2 gene, results from a G to T substitution at nucleotide position 1556. The arginine at codon 519 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been identified in a breast and/or ovarian cancer cohort, however, it's also been identified in the control cohort (Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170:189-196; Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000198277 SCV000254931 uncertain significance Familial cancer of breast 2020-11-02 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 Health, Inc RCV000116007 SCV000537516 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-27 criteria provided, single submitter clinical testing This missense variant replaces arginine with leucine at codon 519 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 29470806), as well as in an unaffected control individual (PMID: 21244692). This variant has been identified in 54/264444 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.
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; Bone osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Division of Medical Genetics, University of Washington RCV000198277 SCV001424821 uncertain significance Familial cancer of breast 2019-04-01 criteria provided, single submitter clinical testing To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an allele frequency of 0.000026 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/). Thus, it is unknown at this time whether this variant increases cancer risk.
Mayo Clinic Laboratories, Mayo Clinic RCV000586195 SCV001715366 uncertain significance not provided 2021-02-16 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357730 SCV001553286 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.Arg519Leu variant was not identified in the literature however alternate substitutions at the same amino acid position (R519Q/R519G) were identified in epithelial ovarian cancers and these amino acid substitutions were localized to the nuclear localization signal region; it is suggested that mutations in this region could adversely affect the nuclear import of CHEK2, reduce the protein level of effective and functional CHEK2, and impact CHEK2 associated repair pathways (Ow 2014). The variant was also identified in dbSNP (ID: rs587780180) “With Uncertain significance” allele, and ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Counsyl, and Color Genomics Inc). The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. Although the p.Arg519 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Leu variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000586195 SCV001906463 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000586195 SCV001959651 uncertain significance not provided no assertion criteria provided clinical testing

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