Submission Details

PTEN gene encodes a phosphatidylinositol-3,4,5-trisphosphate 3 (PIP3)-phosphatase, which blocks phosphatidylinositol 3 kinase (PI3K) signaling by inhibiting PIP3 dependent processes such as the membrane recruitment and activation of AKT, therefore inhibiting cell survival, growth, and proliferation. In 1997, Steck et al. (PMID: 9090379) first identified PTEN gene and reported the association of germline PTEN variants with multiple cancer types, including breast cancer, kidney carcinoma and glioma. The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and PTEN-related Proteus-like syndrome. The phenotypes include macrocephaly, autism or developmental delay, intestinal hamartomatous polyposis, lipomas, pigmented macules of the glans penis, and a high risk for benign and malignant tumors of the thyroid, breast, kidney, and endometrium. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern. Therefore, these phenotypes have been lumped into this curation. The mechanism of pathogenicity is reported to be loss of function. Eight variants (nonsense, frameshift, and missense) that have been reported in 11 probands in 4 publications (PMIDs: 17526800, 22595938, 22628360, 36082652) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 Points) has been reached. This gene-disease relationship is also supported by experimental evidence, including in vitro functional assays and animal models (6 Points, PMIDs: 9356475, 9393738, 9778245, 21194675, 21343951, 21828076, 23066114). This experimental evidence demonstrates that PTEN is a protein phosphatase that exhibits functional and specific growth-suppressing activity. Additionally, heterozygous mutant mice demonstrate noticeable increased cell proliferation and significant macrocephaly as a result of megancephaly. A spectrum of immune phenotypes is associated with PTEN hamartoma tumor syndrome (PHTS), ranging from asymptomatic lymphopenia, to lymphoid hyperplasia, autoimmunity, and immunodeficiency (PMID: 31501268, 28523199, 26246517). While a majority of patients with PHTS do not present with immunodeficiency or immune dysregulation, many show evidence of subclinical immunological abnormalities such as reduced total numbers of CD4+ T cells, inverted CD4:CD8 ratio, or abnormal immunoglobulin subclasses (PMID: 31501268). The B cell phenotype is highly variable, with increased numbers of specific B cell subsets or increased immunoglobulin levels, in contrast to most antibody deficiencies where there is hypogammaglobulinemia and/or B cell deficiency. Autoimmune disorders, including Hashimoto's thyroiditis, celiac disease, autoimmune colitis, and autoimmune hemolytic anemia, have been reported in 29% of 79 PHTS patients in one study (PMID: 27477328). Mouse models of Pten loss-of-function recapitulate the patient immune phenotypes including hypergammaglobulinemia and autoimmunity (10497129) and impaired class-switch recombination and autoantibody production (PMID: 12615906). In summary, there is definitive evidence supporting the relationship between PTEN and autosomal dominant PTEN hamartoma tumor syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally evaluated as definitive by the PTEN GCEP on 10/09/2017. Secondary contributor evidence was provided by the PIRD GCEP. In summary, there is Definitive evidence to support this gene-disease relationship. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This re-curation as definitive was approved by the ClinGen Hereditary Cancer GCEP on 04/05/2024 (SOP Version 10).