ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.520G>A (p.Val174Met) (rs780052789)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164246 SCV000214870 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-18 criteria provided, single submitter clinical testing The p.V174M variant (also known as c.520G>A), located in coding exon 3 of the CDK4 gene, results from a G to A substitution at nucleotide position 520. The valine at codon 174 is replaced by methionine, an amino acid with highly similar properties. T<span style="background-color:initial">his amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.<span style="background-color:initial"> Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000530838 SCV000637375 uncertain significance Hereditary melanoma 2020-05-05 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 174 of the CDK4 protein (p.Val174Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs780052789, ExAC 0.004%). This variant has not been reported in the literature in individuals with CDK4-related disease. 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.
Mendelics RCV000709231 SCV000838662 uncertain significance Cutaneous malignant melanoma 3 2018-07-02 criteria provided, single submitter clinical testing
GeneDx RCV001567127 SCV001790762 uncertain significance not provided 2019-09-25 no assertion criteria provided clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27050151, 28360267, 25617745)

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