ClinVar Miner

Submissions for variant NM_006218.4(PIK3CA):c.3202_3205delinsCTGATAACTGAGAAAATAACTGATAAAATGAAACTGA (p.Asn1068_Ter1069delinsLeuIleThrGluLysIleThrAspLysMetLysLeuArg)

dbSNP: rs2108430158
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV001533202 SCV001745390 pathogenic Lymphatic malformation 2021-07-06 no assertion criteria provided clinical testing A novel deletion-insertion variant was identified in the last exon of PIK3CA (NM_006218.4:c.3202_3206delAACTGinsCTGATAACTGAGAAAATAACTGATAAAATGAAACTGAGA, p.Asn1068Leufs*16). This variant was identified in ~1% of reads (n=1,382), consistent with somatic origin. This variant is not reported in the literature, control population database (gnomAD). The deletion of 5 nucleotides and insertion of 39 nucleotides causes a translation frameshift which substitutes the last C-terminal amino acid of the normal length protein, asparagine (N) for leucine (L) and extends the protein by 16 codons (N* > LITEKITDKMKLRKR*). While this variant has not been reported before, other pathogenic PIK3CA variants that extend the length of the protein are reported (PMID: 15608678, 27631024, ClinVar, COSMIC, cBioPortal). In one report, 50% of hepatocellular carcinomas had a different variant (c.3203dupA) that also changed the last C-terminal amino acid (N) and extended the protein by 3 amino acids (N* > KLKR*) (PMID: 15608678). The functional effect of the p.Asn1068Leufs*16 variant on the autonomous activation and enhancement of the PI3K-AKT-mTOR pathway is unknown. Somatic PIK3CA mutations are the most common cause of isolated lymphatic malformations (LMs) and disorders in which LM is a component feature (PMID: 31536475, 25681199, 29985963; NBK153722). The recently defined PIK3CA-related overgrowth spectrum (PROS) disorders represent clinically recognizable conditions, typically discerned at birth or during early childhood, and are associated with cutaneous, vascular, skeletal and cerebral anomalies, as well as focal or segmental overgrowth of the body. PIK3CA variants associated with PROS overlap those reported as oncogenic variants found in multiple tumor types (COSMIC and cBioPortal Databases). Clinical investigation is underway to evaluate targeted therapies in lesional tissue harboring a PIK3CA mutation.

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