ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.497G>C (p.Ser166Thr) (rs876660536)

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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 RCV000221479 SCV000278054 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-31 criteria provided, single submitter clinical testing Thep.S166Tvariant (also known as c.497G>C), located in coding exon 3 of theCDK4gene, results from a G to C substitution at nucleotide position 497. Theserineat codon 166 is replaced bythreonine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single NucleotidePolymorphisms(dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 17000 alleles tested) in our clinical cohort. 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 for this variant is limited at this time, the clinical significance of p.S166T remains unclear.
Invitae RCV001306378 SCV001495749 uncertain significance Hereditary melanoma 2020-09-01 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 166 of the CDK4 protein (p.Ser166Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 233634). 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.

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