ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.444+2T>C (rs560596101)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483398 SCV000572152 pathogenic not provided 2016-10-27 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.444+2T>C or IVS3+2T>C and consists of a T>C nucleotide substitution at the +2 position of intron 3 of the CHEK2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Although this variant has not, to our knowledge, been reported in the literature, different nucleotide changes also resulting in loss of the canonical splice donor site, c.444+1G>T and c.444+1G>A, have been reported as pathogenic and observed in individuals with breast, pancreatic and prostate cancer (Dong 2003, Kleibl 2008, Cybulski 2006, Bak 2014, Lener 2016). Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000543761 SCV000633188 likely pathogenic Familial cancer of breast 2017-06-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the CHEK2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). 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: 422638). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). 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.
Ambry Genetics RCV000562639 SCV000661735 likely pathogenic Hereditary cancer-predisposing syndrome 2016-04-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Fulgent Genetics,Fulgent Genetics RCV000763474 SCV000894256 pathogenic Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 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.