ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.625C>T (p.Arg209Cys) (rs140644696)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001086259 SCV000166201 likely benign Hereditary melanoma 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130933 SCV000185845 likely benign Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;No disease association in small case-control study;Other data supporting benign classification
GeneDx RCV000586938 SCV000210930 uncertain significance not provided 2021-05-17 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with melanoma, pancreatic, breast, and other cancers (Tung 2015, Zhang 2015, Borroni 2017, Chaffee 2018, Tsai 2019); This variant is associated with the following publications: (PMID: 26252490, 26534844, 28060055, 25801821, 28380455, 26580448, 28726808, 25186627, 27640074, 30374176, 33281875)
Counsyl RCV000409800 SCV000488928 uncertain significance Cutaneous malignant melanoma 3 2016-07-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235157 SCV000601007 uncertain significance not specified 2017-05-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235157 SCV000695320 likely benign not specified 2021-07-19 criteria provided, single submitter clinical testing Variant summary: CDK4 c.625C>T (p.Arg209Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251492 control chromosomes, predominantly within north-western European- (at a frequency of 0.0008) and Swedish European subpopulations (at a frequency of 0.0008) in the gnomAD database (v2.1). These observed subpopulation frequencies are approximately 40 fold higher than the estimated maximal expected allele frequency for a pathogenic variant in CDK4 causing Cutaneous Malignant Melanoma phenotype (i.e. 8e-04 vs. 2e-05), strongly suggesting that the variant is a benign polymorphism found primarily in European subpopulations. The variant, c.625C>T, has been reported in the literature in an individual affected with melanoma (Borroni 2017), and other individuals affected with pancreatic- (Chaffee 2018) and breast cancer (Li 2016, Tung 2015), although with limited information (i.e. lack of co-occurrence and cosegregation data); moreover, two of these breast cancer cases were of western/northern European ancestry. These reports therefore do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation and classified the variant as VUS (n=5) and likely benign (n=2). At-least one additional submitter has re-classified this variant from a VUS to likely benign since its previous evaluation. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761111 SCV000891027 uncertain significance Hepatoblastoma 2016-12-05 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000130933 SCV000787990 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-02 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000586938 SCV001798568 uncertain significance not provided no assertion criteria provided 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.