ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.349A>G (p.Ile117Val) (rs776343973)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566485 SCV000669134 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-02 criteria provided, single submitter clinical testing The p.I117V variant (also known as c.349A>G), located in coding exon 2 of the CDK4 gene, results from an A to G substitution at nucleotide position 349. The isoleucine at codon 117 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in an individual affected with colorectal cancer (Yurgelun MB et al. J. Clin. Oncol., 2017 Apr;35:1086-1095). 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.
Invitae RCV001053516 SCV001217783 uncertain significance Hereditary melanoma 2020-06-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 117 of the CDK4 protein (p.Ile117Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs776343973, ExAC 0.004%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 483303). 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.

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