ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.352A>C (p.Lys118Gln) (rs772689692)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474609 SCV000547952 uncertain significance Hereditary melanoma 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 118 of the CDK4 protein (p.Lys118Gln). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamine. This variant is present in population databases (rs772689692, ExAC 0.001%) but has not been reported in the literature in individuals with a 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000487233 SCV000564848 uncertain significance not provided 2015-02-02 criteria provided, single submitter clinical testing This variant is denoted CDK4 c.352A>C at the cDNA level, p.Lys118Gln (K118Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDK4 Lys118Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. CDK4 Lys118Gln occurs at a position that is highly conserved across species and is located in the protein kinase domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CDK4 Lys118Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001020530 SCV001182020 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-12 criteria provided, single submitter clinical testing The p.K118Q variant (also known as c.352A>C), located in coding exon 2 of the CDK4 gene, results from an A to C substitution at nucleotide position 352. The lysine at codon 118 is replaced by glutamine, an amino acid with similar properties. This amino acid position is highly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175469 SCV001339044 uncertain significance not specified 2020-03-26 criteria provided, single submitter clinical testing Variant summary: CDK4 c.352A>C (p.Lys118Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251486 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.352A>C in individuals affected with Cutaneous Malignant Melanoma and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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