Submission Details

AKT1 was first reported in relation to autosomal dominant Cowden syndrome in 2013 (Orloff et al., PMID: 23246288). AKT1 has been noted to be associated with Cowden syndrome and Proteus syndrome. Cowden syndrome is characterized by macrocephaly, trichilemmomas, and papillomatous papules, and benign and malignant tumors of the thyroid, breast, kidney and endometrium. Most people with Cowden syndrome carry a variant in the PTEN gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanism and inheritance pattern of AKT1-associated Cowden syndrome and Proteus syndrome. Therefore, the disease entities have been split into separate curations. The Proteus syndrome assertion will be curated separately by the ClinGen Brain Malformations GCEP. Two missense variants in AKT1 that have been reported in two probands in one publication (PMID: 23246288) are included in this curation. This gene-disease relationship is also supported by in vitro functional assays demonstrating the effects of PTEN signaling on AKT1 activity in Cowden syndrome patients (PMIDs: 21194675, 22962422). In summary, there is limited evidence supporting the relationship between AKT1 and autosomal dominant Cowden syndrome. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on November 12, 2024 (SOP Version 11).