ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.431A>G (p.Glu144Gly) (rs863224603)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195700 SCV000254231 uncertain significance Hereditary melanoma 2020-08-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 144 of the CDK4 protein (p.Glu144Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 216269). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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 RCV000235588 SCV000293891 uncertain significance not provided 2016-11-22 criteria provided, single submitter clinical testing This variant is denoted CDK4 c.431A>G at the cDNA level, p.Glu144Gly (E144G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAG>GGG). This variant was observed a cohort of 1250 individuals with personal history of Lynch syndrome-associated cancer and/or polyps undergoing cancer panel genetic testing (Yurgelun 2015). CDK4 Glu144Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDK4 Glu144Gly occurs at a position that is conserved across species and is located within the protein kinase domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether CDK4 Glu144Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000561657 SCV000669102 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-30 criteria provided, single submitter clinical testing The p.E144G variant (also known as c.431A>G), located in coding exon 3 of the CDK4 gene, results from an A to G substitution at nucleotide position 431. The glutamic acid at codon 144 is replaced by glycine, an amino acid with similar properties. 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.

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