ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 21
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000116009 SCV000185901 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-24 criteria provided, single submitter clinical testing The p.E64K variant (also known as c.190G>A), located in coding exon 1 of the CHEK2 gene, results from a G to A substitution at nucleotide position 190. The glutamic acid at codon 64 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in multiple cohorts of breast, ovarian and prostate cancer patients (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Desrichard A et al. Breast Cancer Res. 2011;13:R119; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535; Tsai GJ et al. Genet. Med. 2019 06;21:1435-1442; Girard E et al. Int. J. Cancer. 2019 04;144:1962-1974). Functional studies in a human-cell-based kinase assay indicated p.E64K confers partial, or reduced CHK2 protein function compared to the wild-type protein (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7). In a yeast-based, cell proliferation assay, literature results conflict as to whether this alteration will be damaging or tolerated (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Delimitsou A et al. Hum. Mutat. 2019 05;40:631-648). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000199067 SCV000254934 likely pathogenic Familial cancer of breast 2020-10-29 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000210191 SCV000266168 likely pathogenic Breast and colorectal cancer, susceptibility to 2019-09-09 criteria provided, single submitter clinical testing This variant has been shown to partially reduce CHEK2 protein kinase activity (PMID 16835864). In a different functional assay system the CHEK2 p.E64K variant was also shown to impact CHEK2 protein function (PMID 22419737). This variant occurs at a position that is moderately evolutionarily conserved and is predicted to be probably damaging by computer analysis with PolyPhen2 and SIFT. This analysis was performed in conjunction with the family studies as part of the University of Washington Find My Variant study.
Counsyl RCV000199067 SCV000488777 uncertain significance Familial cancer of breast 2016-06-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212407 SCV000601160 uncertain significance not provided 2020-08-02 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212407 SCV000806876 uncertain significance not provided 2017-11-29 criteria provided, single submitter clinical testing
GeneKor MSA RCV000116009 SCV000821997 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000199067 SCV000839503 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212407 SCV000892320 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000116009 SCV000902646 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-13 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 64 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 that this variant is deleterious to function in cell based, kinase assays (PMID: 31050813, 16835864), but shows inconsistent results in yeast based DNA damage repair assays (PMID 22419737, 30851065). This variant has been reported in individuals affected with prostate cancer (PMID: 12533788, 16835864, 16941491, 24082139, 27433846, 31220302), breast cancer (PMID: 22114986, 25503501, 26845104, 26976419, 27616075, 31050813, 26681312), colorectal cancer (PMID: 27696107, 28135145, 26681312), ovarian cancer (PMID: 27779110, 26681312) and pancreatic cancer (PMID: 26845104). This variant occurs at an elevated frequency in the general population and has been identified in 45/282814 chromosomes (39/129148 Non-Finnish European chromosomes) by the Genome Aggregation Database (gnomAD). This variant has also been identified in 11 of 9884 females over age 70 without personal history of cancer (FLOSSIES database, https://whi.color.com/variant/22-29130520-C-T). Based on the available evidence, this variant is classified as Likely Pathogenic. Although the penetrance of this variant has not been determined, the elevated frequency in population databases and population matched controls (gnomAD, FLOSSIES, PMID 31050813) suggests that this variant may be of lower than expected penetrance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Illumina Clinical Services Laboratory,Illumina RCV001149533 SCV001310491 uncertain significance CHEK2-Related Cancer Susceptibility 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV000199067 SCV001429610 uncertain significance Familial cancer of breast 2019-12-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287335 SCV001474010 uncertain significance none provided 2020-04-03 criteria provided, single submitter clinical testing The CHEK2 c.190G>A; p.Glu64Lys variant (rs141568342) is reported in the literature in individuals with breast, ovarian, or prostate cancer (Carter 2018, Desrichard 2011, Dong 2003). This variant is also reported by multiple laboratories in the ClinVar database (Variation ID: 128068). A yeast functional assay suggests this variant is benign (Delimitsou 2019), but other functional assays report this variant causes reduced kinase activity and reduced DNA damage response (Kleiblova 2019, Roeb 2012, Wu 2006). This variant is found in the general population with an overall allele frequency of 0.02% (45/282814 alleles) in the Genome Aggregation Database. The glutamate at codon 64 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Given the currently available information, the clinical significance of this variant is uncertain at this time. REFERENCES Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. Delimitsou A et al. Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat. 2019 May;40(5):631-648. Desrichard A et al. CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Cancer Res. 2011;13(6):R119. Dong X et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003 Feb;72(2):270-80. Epub 2003 Jan 17. Kleiblova P et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019 Oct 1;145(7):1782-1797. Roeb W et al. Response to DNA damage of CHEK2 missense mutations in familial breast cancer. Hum Mol Genet. 2012 Jun 15;21(12):2738-44. Wu X et al. Characterization of CHEK2 mutations in prostate cancer. Hum Mutat. 2006 Aug;27(8):742-7.
True Health Diagnostics RCV000116009 SCV000805259 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-16 no assertion criteria provided 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV001149533 SCV001446371 likely pathogenic CHEK2-Related Cancer Susceptibility 2019-09-09 no assertion criteria provided research
CZECANCA consortium RCV001270935 SCV001451739 likely pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided case-control
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356247 SCV001551362 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.Glu64Lys variant was identified in 16 of 30462 proband chromosomes (frequency: 0.0005) from individuals or families with breast, prostate, and colon cancer and was also identified in 1 of 1872 control chromosomes from healthy individuals (Desrichard 2011, Balmana 2016, Mandelker 2017, Susswein 2015, Rohlin 2016, Dong 2003, Wu 2006, Kraus 2017, Shirts 2016, Havranek 2015). The variant was also identified in dbSNP (ID: rs141568342) as "With Likely Pathogenic allele", in ClinVar (classified as likely pathogenic by GeneDx and a variant of uncertain significance by Ambry, Invitae, UWDLP, Counsyl and QDNISJC), and Zhejiang University database (3x). The variant was not identified in Cosmic or MutDB databases. The variant was identified in control databases in 44 of 277158 chromosomes at a frequency of 0.00016 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 24020 chromosomes (freq: 0.00008), Latino in 2 of 34420 chromosomes (freq: 0.00006), European Non-Finnish in 38 of 126668 chromosomes (freq: 0.0003), and South Asian in 2 of 30782 chromosomes (freq: 0.00007). The variant was not observed in the “Other”, Ashkenazi Jewish, East Asian or Finnish populations. Functional analyses suggesting that this variant is pathogenic have shown reduced phosphorylation and kinase activity as well as loss of DNA damage response (Wu 2006, Roeb 2012). The p.Glu64Lys residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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.
GenomeConnect - Invitae Patient Insights Network RCV000212407 SCV001749676 not provided not provided no assertion provided phenotyping only Variant interpreted as Likely pathogenic and reported on 01-08-2018 by Color. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.