PIK3CA related overgrowth syndrome: genes and variants

Genes linked to PIK3CA related overgrowth syndrome

• PIK3CA: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

  Its p110-alpha catalytic activity generates PIP3 and activates AKT-dependent growth, survival, and metabolic signaling downstream of many receptors. Activating variants are frequent cancer drivers and, when present mosaically during development, can cause PIK3CA-related overgrowth spectrum.

  30 disease-causing and 4 uncertain variants in PIK3CA are linked to PIK3CA related overgrowth syndrome.

Where PIK3CA related overgrowth syndrome variants cluster

• PIK3CA C2 PI3K-type (positions 330–487): 9 of 30 disease-causing changes, 2.0× more than its size predicts.
• PIK3CA PI3K-ABD (positions 16–105): 5 of 30 disease-causing changes, 2.0× more than its size predicts.

Known disease-causing variants in PIK3CA related overgrowth syndrome

Same protein, different disease

• Cowden syndrome is also caused by PIK3CA variants; they fall partly in the same places as the PIK3CA related overgrowth syndrome variants (23 disease-causing).
• Megalencephaly-capillary malformation-polymicrogyria syndrome is also caused by PIK3CA variants; they fall partly in the same places as the PIK3CA related overgrowth syndrome variants (22 disease-causing).
• Ovarian neoplasm is also caused by PIK3CA variants; they fall in the same places as the PIK3CA related overgrowth syndrome variants (5 disease-causing).
• PIK3CA constitutional syndrome is also caused by PIK3CA variants; they fall partly in the same places as the PIK3CA related overgrowth syndrome variants (4 disease-causing).
• Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes is also caused by PIK3CA variants; they fall mostly in different places as the PIK3CA related overgrowth syndrome variants (4 disease-causing).

Diseases related to PIK3CA related overgrowth syndrome

• Noonan syndrome, also linked to PIK3CA
• Cowden syndrome, also linked to PIK3CA
• Ovarian cancer, also linked to PIK3CA
• Familial cancer of breast, also linked to PIK3CA
• Megalencephaly-capillary malformation-polymicrogyria syndrome, also linked to PIK3CA
• Colorectal cancer, also linked to PIK3CA
• Gastric cancer, also linked to PIK3CA
• Malignant tumor of urinary bladder, also linked to PIK3CA
• Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, also linked to PIK3CA
• Non-small cell lung carcinoma, also linked to PIK3CA
• Ovarian neoplasm, also linked to PIK3CA
• Carcinoma of colon, also linked to PIK3CA

Frequently asked questions

Which genes are linked to PIK3CA related overgrowth syndrome?

In CATVariant, PIK3CA related overgrowth syndrome is linked to 1 analyzed protein: PIK3CA (Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform).

How many genetic variants are linked to PIK3CA related overgrowth syndrome?

34 variants: 30 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 4 are of uncertain significance or have conflicting reports.

Which uncertain variants in PIK3CA related overgrowth syndrome look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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