ClinVar Miner

Submissions for variant NM_006218.4(PIK3CA):c.2530T>C (p.Cys844Arg)

gnomAD frequency: 0.00001  dbSNP: rs756890248
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
New York Genome Center RCV001291738 SCV001480330 uncertain significance Cowden syndrome 5 2019-11-26 criteria provided, single submitter clinical testing The inherited c.2530T>C, p.Cys844Arg missense variant in the PIK3CA gene has not been reported in the available literature. The variant maps to the kinase domain,which acts as a lipid-binding interface of the p110α protein [PMID: 30197175]. The variant has 0.0008% allele frequency in the gnomAD database (2 out of 248,178 heterozygous alleles), indicating this is a rare allele. In silico tools, SIFT, PolyPhen, REVEL,and CADD predict conflicting evidence of pathogenicity. Based on the available evidence, the c.2530T>C, p.Cys844Arg variant in the PIK3CA gene is classified as a variant of uncertain significance.
Invitae RCV001313173 SCV001503655 uncertain significance Cowden syndrome 2021-08-31 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 844 of the PIK3CA protein (p.Cys844Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs756890248, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with PIK3CA-related conditions. 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. 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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