ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.460G>C (p.Val154Leu) (rs563692823)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197494 SCV000254232 uncertain significance Hereditary melanoma 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 154 of the CDK4 protein (p.Val154Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs563692823, ExAC 0.006%). This variant has been observed in individual(s) with melanoma, suspected Lynch syndrome, and in an individual undergoing genetic testing for hereditary cancer (PMID: 26800492, 31159747, 25980754). ClinVar contains an entry for this variant (Variation ID: 216270). 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.
GeneDx RCV000236001 SCV000292533 uncertain significance not provided 2017-03-23 criteria provided, single submitter clinical testing This variant is denoted CDK4 c.460G>C at the cDNA level, p.Val154Leu (V154L) at the protein level, and results in the change of a Valine to a Leucine (GTC>CTC). CDK4 Val154Leu has been observed in at least one individual with a personal and family history of melanoma and another who underwent multigene hereditary cancer panel testing due to a personal history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015, Muller 2016). CDK4 Val154Leu was observed at an allele frequency of 0.006% (4/66,738) in individuals of European (Non-Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. CDK4 Val154Leu occurs at a position that is conserved across species and is located within the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether CDK4 Val154Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000565727 SCV000664580 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-14 criteria provided, single submitter clinical testing The p.V154L variant (also known as c.460G>C), located in coding exon 3 of the CDK4 gene, results from a G to C substitution at nucleotide position 460. The valine at codon 154 is replaced by leucine, an amino acid with highly similar properties. In one study of melanoma patients from Austria, this variant was seen in 1/232 patients, who had sequencing of the CDK4 gene; this was a female diagnosed with melanoma at age 42 with a family history of melanoma in her father (Müller C et al. Br. J. Dermatol., 2016 Jun;174:1308-17). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneKor MSA RCV000565727 SCV000821980 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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