ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.245G>A (p.Arg82Gln) (rs3211612)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206239 SCV000259629 uncertain significance Hereditary melanoma 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 82 of the CDK4 protein (p.Arg82Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs3211612, ExAC 0.02%). This variant has been observed in an individual affected with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 219640). 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 RCV000477988 SCV000568163 uncertain significance not provided 2016-06-01 criteria provided, single submitter clinical testing This variant is denoted CDK4 c.245G>A at the cDNA level, p.Arg82Gln (R82Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDK4 Arg82Gln 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 Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. CDK4 Arg82Gln occurs at a position that is not conserved and is located in 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 Arg82Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573084 SCV000669087 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-07 criteria provided, single submitter clinical testing The p.R82Q variant (also known as c.245G>A), located in coding exon 2 of the CDK4 gene, results from a G to A substitution at nucleotide position 245. The arginine at codon 82 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in 1/450 patients with colorectal cancer diagnosed under the age of 50 who were tested with a multi-gene panel, and p.R82Q was called a variant of uncertain significance by the study authors (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). 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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