ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs587780180
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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586195 SCV000149916 uncertain significance not provided 2023-04-20 criteria provided, single submitter clinical testing Observed in individuals with colon, breast, ovarian, and other cancers, as well as in control groups (Singh et al., 2018; Dutil et al., 2019; Girard et al., 2019; Weitzel et al., 2019; Akcay et al., 2020; Erdem et al., 2020; Abdel-Razeq et al., 2022; Guindalini et al., 2022; Yngvadottir et al., 2022); Published functional studies are inconclusive: intermediate growth rate in response to DNA damage (Delimitsou et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31422574, 24879340, 21244692, 26787654, 28102005, 28166811, 29470806, 31159747, 30303537, 31780696, 32283892, 32906215, 22419737, 32659967, 30851065, 35402282, 32658311, 31206626, 35127508, 35264596, 35441217, 29522266, 28779002)
Ambry Genetics RCV000116007 SCV000186581 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-23 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 numerous colon, breast and/or ovarian cancer cohorts, however, it has also been identified in healthy control populations (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6; Young EL et al. J Med Genet, 2016 06;53:366-76; Decker B et al. J Med Genet, 2017 11;54:732-741; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170:189-196; Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Erdem HB et al. Turk J Med Sci, 2020 06;50:1015-1021; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295; Bakos B et al. BMC Cancer, 2021 Jun;21:706; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This alteration behaved as indeterminate or semi-functional in in vivo, yeast-based assays (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648; Dutil J et al. Sci Rep, 2019 11;9:17769). 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 2024-02-01 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 519 of the CHEK2 protein (p.Arg519Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29470806, 32658311). ClinVar contains an entry for this variant (Variation ID: 128066). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 Diagnostics, LLC DBA Color Health RCV000116007 SCV000537516 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-14 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). Functional studies have shown this variant to result in a partial loss of CHEK2 DNA damage repair activity in a yeast-based assay (PMID: 30851065) and normal kinase activity in an in vitro assay (PMID: 31780696). This variant has been reported in individuals affected with breast cancer (PMID: 29470806, 31780696, 35402282), ovarian cancer (PMID: 32546565), as well as in unaffected control individuals (PMID: 21244692, 32546565). In a large breast cancer case-control study, this variant has been observed in 13/60453 cases and 7/53454 controls (OR=1.642, 95%CI 0.655 to 4.116, p-value=0.3720; PMID: 33471991). 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 2021-10-26 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 0.00023 in 235260 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Breast Cancer (0.00023 vs 0.00031), allowing no conclusion about variant significance. c.1556G>T has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with Breast and/or Lynch associated tumors/colorectal cancer (example, Singh_2018, Young_2016, Weitzel_2019, deCarvalho_2020, Vargas-Parra_2020, Ackay_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on protein function (Delimitsou_2019). The most pronounced variant effect results in intermediate levels of normal activity evaluating MMS (methyl-methanesulfonate) induced DNA damage repair in a yeast based functional assay. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified 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 RCV003492503 SCV000839452 likely benign Hereditary cancer 2024-01-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586195 SCV000889324 uncertain significance not provided 2023-06-03 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 29470806 (2016), 32658311 (2021), 32906215 (2020), 30303537 (2019), 31159747 (2019), and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2)) and renal cell carcinoma (PMID: 35441217 (2022)), as well as healthy individuals (PMIDs: 21244692 (2011) and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2)). The frequency of this variant in the general population, 0.00017 (21/123898 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
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
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000586195 SCV002009505 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798353 SCV002043397 uncertain significance Breast and/or ovarian cancer 2023-05-05 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000586195 SCV002544708 likely benign not provided 2022-06-01 criteria provided, single submitter clinical testing CHEK2: BP4, BS3:Supporting
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV002291560 SCV002584737 uncertain significance Predisposition to cancer 2022-07-13 criteria provided, single submitter clinical testing The CHEK2 c.1556G>T (p.Arg519Leu) missense change has a maximum subpopulation frequency of 0.046% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has been reported in individuals with breast and/or ovarian cancer, colorectal cancer, and Lynch syndrome (PMID: 29470806, 29522266, 30303537, 31780696, 32283892, 32659967, 34130653, 35127508, 35402282). The in silico tool REVEL predicts a benign effect on protein function, and functional studies are inconclusive. This variant was characterized as semi-functional (intermediate) in a yeast-based assay evaluating DNA damage response (PMID: 30851065), whereas kinase activity and phosphorylation in a transfected cell line was comparable to the wild-type (PMID: 31780696). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000198277 SCV003936139 uncertain significance Familial cancer of breast 2023-07-05 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) by multiple clinical diagnostic laboratories after 2014 classify this variant as uncertain significant variant .In addition, this alteration is predicted to be tolerated by in silico analysis. 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.
Myriad Genetics, Inc. RCV000198277 SCV004020219 likely benign Familial cancer of breast 2023-03-09 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000212476 SCV004027044 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004529941 SCV004114830 uncertain significance CHEK2-related disorder 2023-07-25 criteria provided, single submitter clinical testing The CHEK2 c.1556G>T variant is predicted to result in the amino acid substitution p.Arg519Leu. This variant has been identified in individuals with breast and/or ovarian cancer (Table S1, Young et al. 2016. PubMed ID: 26787654; Table S5, Decker et al. 2017. PubMed ID: 28779002; Table S1, Hauke et al. 2018. PubMed ID: 29522266; Table S4, Singh et al. 2018. PubMed ID: 29470806; Table S6, Akcay et al. 2020. PubMed ID: 32658311), individuals with a personal and/or family history of hereditary cancer (Table S6, Tsaousis et al. 2019. PubMed ID: 31159747; Table 2, Dutil et al. 2019. PubMed ID: 31780696; Table S1, Vargas-Parra et al. 2020. PubMed ID: 32906215), an individual with colorectal cancer (Table 2, Erdem et al. 2020. PubMed ID: 32283892), as well as in a control individual (Table S1, Le Calvez-Kelm et al. 2011. PubMed ID: 21244692). The results of in vitro and in vivo experimental studies of this variant are inconclusive (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065; Dutil et al. 2019. PubMed ID: 31780696). This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29083961-C-A) and is interpreted as uncertain significance by the vast majority of clinical laboratories in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/128066/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics RCV000198277 SCV004215836 uncertain significance Familial cancer of breast 2023-10-31 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000116007 SCV004228090 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-14 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000586195 SCV001959651 uncertain significance not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000586195 SCV001978655 uncertain significance not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000586195 SCV002036710 uncertain significance not provided no assertion criteria provided clinical testing

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