ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1597A>G (p.Thr533Ala) (rs562517792)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130825 SCV000185721 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000199838 SCV000253483 likely benign Familial cancer of breast 2017-10-26 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415925 SCV000493190 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing
GeneDx RCV000415925 SCV000564879 uncertain significance not provided 2018-09-21 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1597A>G at the cDNA level, p.Thr533Ala (T533A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant has been observed in at least one individual with advanced cancer (Mandelker 2017). A mutant Chk2 construct containing this variant was demonstrated to undergo normal Chk2 autophosphorylation by an in vitro kinase assay (Wu 2003). CHEK2 Thr533Ala was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 Thr533Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130825 SCV000910751 likely benign Hereditary cancer-predisposing syndrome 2016-10-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781307 SCV000919227 uncertain significance not specified 2018-09-28 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1597A>G (p.Thr533Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 260106 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. However, pseudogene interference cannot be ruled out. The variant, c.1597A>G, has been reported in the literature in one individual with a melanoma arising in a congenital nevus of Ito, however germline or somatic status was not clearly established. This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One publication reports experimental evidence showing kinase activity comparable to wild-type associated with this variant (Wu_2003). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS x3, likely benignx1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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.