Cowden syndrome: genes and variants

Genes linked to Cowden syndrome

• PTEN: Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN

  A lipid and protein phosphatase that removes phosphate groups from signaling molecules, especially PIP3. By opposing the PI3K-AKT pathway, it limits cell growth and survival signals, and PTEN variants are associated with Cowden syndrome and multiple cancers.

  41 disease-causing and 34 uncertain variants in PTEN are linked to Cowden 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.

  23 disease-causing and 216 uncertain variants in PIK3CA are linked to Cowden syndrome.

• SDHD: Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial

  It provides a membrane-anchoring component of succinate dehydrogenase and is required for normal complex II electron transfer. Germline loss-of-function variants, often showing a parent-of-origin effect, strongly predispose to head-and-neck paragangliomas and pheochromocytomas.

  11 disease-causing and 156 uncertain variants in SDHD are linked to Cowden syndrome.

• AKT1: RAC-alpha serine/threonine-protein kinase

  It integrates PI3K-dependent growth-factor signals to promote cell survival, proliferation, glucose metabolism, and protein synthesis. Somatic activating variants occur in multiple cancers, while mosaic activation, especially E17K, causes Proteus syndrome.

  3 disease-causing and 157 uncertain variants in AKT1 are linked to Cowden syndrome.

Weakly linked (only a few uncertain records): SDHB.

Where Cowden syndrome variants cluster

• PTEN Phosphatase tensin-type (positions 14–185): 37 of 41 disease-causing changes, 2.1× more than its size predicts.
• SDHD Transmembrane (positions 91–111): 7 of 11 disease-causing changes, 4.8× more than its size predicts.
• PIK3CA PI3K-ABD (positions 16–105): 3 of 23 disease-causing changes, 1.6× more than its size predicts.

Known disease-causing variants in Cowden syndrome

Showing 60 of 78.

Uncertain variants in Cowden syndrome that look disease-causing

Which prediction tools work for Cowden syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• ESM1b (LLR): 99 out of 100
• AlphaMissense: 98 out of 100
• PolyPhen-2: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 96 out of 100
• CADD: 94 out of 100
• CATVariant: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 70 out of 100
• DMS / MaveDB: 54 out of 100

Same protein, different disease

• PTEN hamartoma tumor syndrome is also caused by PTEN variants; they fall partly in the same places as the Cowden syndrome variants (147 disease-causing).
• Macrocephaly-autism syndrome is also caused by PTEN variants; they fall partly in the same places as the Cowden syndrome variants (13 disease-causing).
• Glioma susceptibility 1 is also caused by PTEN variants; they fall in the same places as the Cowden syndrome variants (5 disease-causing).
• PIK3CA related overgrowth syndrome is also caused by PIK3CA variants; they fall partly in the same places as the Cowden syndrome variants (30 disease-causing).
• Megalencephaly-capillary malformation-polymicrogyria syndrome is also caused by PIK3CA variants; they fall partly in the same places as the Cowden syndrome variants (22 disease-causing).
• Ovarian neoplasm is also caused by PIK3CA variants; they fall in the same places as the Cowden syndrome variants (5 disease-causing).
• Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes is also caused by PIK3CA variants; they fall partly in the same places as the Cowden syndrome variants (4 disease-causing).
• Pheochromocytoma is also caused by SDHD variants; they fall in the same places as the Cowden syndrome variants (14 disease-causing).
• Paragangliomas with sensorineural hearing loss is also caused by SDHD variants; they fall in the same places as the Cowden syndrome variants (13 disease-causing).
• Carney-Stratakis syndrome is also caused by SDHD variants; they fall in the same places as the Cowden syndrome variants (11 disease-causing).
• Pheochromocytoma/paraganglioma syndrome 5 is also caused by SDHD variants; they fall in the same places as the Cowden syndrome variants (4 disease-causing).

Diseases related to Cowden syndrome

• Familial cancer of breast, also linked to AKT1, PIK3CA and PTEN
• Ovarian cancer, also linked to AKT1 and PIK3CA
• Endometrial carcinoma, also linked to PIK3CA and PTEN
• Noonan syndrome, also linked to PIK3CA
• PTEN hamartoma tumor syndrome, also linked to PTEN
• Pheochromocytoma/paraganglioma syndrome 5, also linked to SDHD
• Pheochromocytoma, also linked to SDHD
• PIK3CA related overgrowth syndrome, also linked to PIK3CA
• Megalencephaly-capillary malformation-polymicrogyria syndrome, also linked to PIK3CA
• Colorectal cancer, also linked to PIK3CA
• Carney-Stratakis syndrome, also linked to SDHD
• Gastric cancer, also linked to PIK3CA

Frequently asked questions

Which genes are linked to Cowden syndrome?

In CATVariant, Cowden syndrome is linked to 4 analyzed proteins: PTEN (Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN), PIK3CA (Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform), SDHD (Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial) and AKT1 (RAC-alpha serine/threonine-protein kinase).

How many genetic variants are linked to Cowden syndrome?

684 variants: 78 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 566 are of uncertain significance or have conflicting reports.

Which uncertain variants in Cowden syndrome look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example PTEN G165E. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Cowden syndrome?

Among tools not trained on clinical labels, ESM1b (LLR) separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 41 disease-causing and 8 harmless variants).

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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