ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.684-4A>T (rs370609910)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130918 SCV000185828 benign Hereditary cancer-predisposing syndrome 2019-04-05 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Other data supporting benign classification;RNA Studies
Invitae RCV001081858 SCV000253071 likely benign Hereditary melanoma 2020-12-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000379030 SCV000380488 benign Cutaneous malignant melanoma 3 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx RCV000435356 SCV000517464 likely benign not specified 2017-11-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587409 SCV000695323 benign not provided 2016-10-21 criteria provided, single submitter clinical testing Variant summary: The CDK4 c.684-4A>T variant involves the alteration of a non-conserved intronic nucleotide with 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicting alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 21/121132 (1/5767), predominantly in the European (Non-Finnish) cohort, 19/66612 (1/3506), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic CDK4 variant of 1/50000. Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of European (Non-Finnish) origin. The variant of interest has been reported in affected individuals via publications, however, cosegregation data was not provided. Clinical diagnostic laboratories have cited the variant with conflicting classifications "uncertain siginficance" or "likely benign," without any additional information to provide an independent evaluation. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign.

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