ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.755G>A (p.Ser252Asn) (rs587781379)

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 RCV000129204 SCV000183949 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient or conflicting evidence
GeneDx RCV000214585 SCV000279244 uncertain significance not provided 2018-06-07 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.755G>A at the cDNA level, p.Ser252Asn (S252N) at the protein level, and results in the change of a Serine to an Asparagine (AGC>AAC). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported in a tumor sample from an individual with neuroblastoma (Padovan-Merhar 2016). CHEK2 Ser252Asn was observed at an allele frequency of 0.1% (18/18,864) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the kinase domain (Cai 2009, Roeb 2012). In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether CHEK2 Ser252Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227256 SCV000289704 uncertain significance Familial cancer of breast 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 252 of the CHEK2 protein (p.Ser252Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs587781379, ExAC 0.1%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with a CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 140932). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000227256 SCV000488892 uncertain significance Familial cancer of breast 2016-07-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765620 SCV000896945 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000129204 SCV000903078 likely benign Hereditary cancer-predisposing syndrome 2016-06-28 criteria provided, single submitter clinical testing

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.