ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.190G>A (p.Glu64Lys) (rs141568342)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116009 SCV000185901 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212407 SCV000892320 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
Color RCV000116009 SCV000902646 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing
Counsyl RCV000199067 SCV000488777 uncertain significance Familial cancer of breast 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000212407 SCV000149918 likely pathogenic not provided 2018-09-10 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.190G>A at the cDNA level, p.Glu64Lys (E64K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has been reported in individuals with personal and/or family history of breast, prostate, or pancreatic cancer (Dong 2003, Wu 2006, Desrichard 2011, Roeb 2012, Kraus 2016, Shirts 2016, Tung 2016, Mandelker 2017). Functional analyses have shown reduced phosphorylation and kinase activity as well as loss of DNA damage response (Wu 2006, Roeb 2012). CHEK2 Glu64Lys was observed at an allele frequency of 0.03% (38/126,668) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the SQ/TQ domain (Bartek 2001, Desrichard 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider CHEK2 Glu64Lys to be a likely pathogenic variant.
GeneKor MSA RCV000116009 SCV000821997 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000199067 SCV000986765 not provided Familial cancer of breast no assertion provided phenotyping only Variant interpretted as Likely pathogenic and reported on 01/08/2018 by GTR ID Color. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Integrated Genetics/Laboratory Corporation of America RCV000505920 SCV000917231 uncertain significance not specified 2017-10-20 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.190G>A (p.Glu64Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). One DNA damage response study using a yeast-based assay showed a lack of response due to the variant (Roeb_2012). This variant was found in 44/277158 control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0003 (38/126668). This frequency is approximately equal to the estimated maximal expected allele frequency of a pathogenic CHEK2 variant in HBOC phenotypes (0.0003125), suggesting this may be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. However, a high-homology CHEK2 pseudogene may confound these results and interpretation must be performed cautiously. This variant was reported in multiple patients with HBOC, prostate cancer, and CRC (Wu_2006, Pritchard_2016, Kraus_2016, Shirts_2016), without strong evidence for pathogenicity, including one report where it co-occurred with likely pathogenic BMPR1A c.969delT, p.Cys323Trpfs*41 and CHEK2 c.470T>C, p.Ille157Thr in one individual with CRC (Rohlin_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a VUS until more definitive functional and clinical data become available.
Invitae RCV000199067 SCV000254934 likely pathogenic Familial cancer of breast 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 64 of the CHEK2 protein (p.Glu64Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs141568342, ExAC 0.03%). This variant has been observed in many individuals with a personal and/or family history of breast, prostate, ovarian, colorectal, thyroid, and pancreatic cancer (PMID: 27616075, 22114986, 27779110, 24082139, 12533788, 26681312, 28135145, 26845104). It has also been observed to segregate with CHEK2-related cancers in several families, although with incomplete penetrance (Invitae, External communication). ClinVar contains an entry for this variant (Variation ID: 128068). Experimental studies have shown that this missense change leads to reduced phosphorylation and partial disruption of CHEK2 kinase activity (PMID: 16835864), as well as loss of DNA damage response (PMID: 22419737). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mendelics RCV000199067 SCV000839503 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000212407 SCV000806876 uncertain significance not provided 2017-11-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505920 SCV000601160 uncertain significance not specified 2017-02-22 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000116009 SCV000805259 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-16 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000210191 SCV000266168 uncertain significance Breast and colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing This variant was shown to partially reduce CHEK2 protein kinase activity (Wu 2006). In a different functional assay system (Roeb 2012) the CHEK2 p.E64K variant was also shown to impact CHEK2 protein function

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