Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clingen PTEN Variant Curation Expert Panel, |
RCV004555587 | SCV005044851 | uncertain significance | PTEN hamartoma tumor syndrome | 2023-10-11 | reviewed by expert panel | curation | NM_000314.8(PTEN):c.49C>G (p.Gln17Glu) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor) PS3_P: Other studies demonstrating lipid phosphatase activity <50% of wild-type or abnormal in vitro cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3_moderate. (PMIDs: 24292679, 29706633). PM2_P: Absent in gnomAD PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. BP4: REVEL score < 0.5 (score=0.498) Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting, 1 pathogenic moderate, 3 pathogenic supporting codes get -1 + 2 + (1*3) points; total is 4 (Uncertain significance). |
| Ambry Genetics | RCV000563631 | SCV000663589 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-07-25 | criteria provided, single submitter | clinical testing | The p.Q17E variant (also known as c.49C>G), located in coding exon 1 of the PTEN gene, results from a C to G substitution at nucleotide position 49. The glutamine at codon 17 is replaced by glutamic acid, an amino acid with highly similar properties. This variant, referred to as c.49C>G, has been detected in a cohort of patients who met clinical diagnostic criteria for Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like (Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23:1538-43). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Gene |
RCV001556501 | SCV001778093 | pathogenic | not provided | 2020-06-16 | criteria provided, single submitter | clinical testing | Reported in association with Cowden or Cowden-like syndrome (Nizialek et al., 2015); Published functional studies demonstrate that Q17E modestly stimulated nuclear localization, increased the PIP3 phosphatase activity of PTEN, and could not rescue developmental defects in PTEN-Dictyostelium cells compared to the wildtype (Nguyen et al., 2014); Published functional studies in cell lines demonstrate that Q17E promotes nuclear localization of PTEN compared to wildtype (Mingo et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29706633, 25669429, 26216063, 24979808) |
| Institute of Medical Genetics and Applied Genomics, |
RCV004553261 | SCV005043788 | likely pathogenic | Macrocephaly-autism syndrome | 2024-05-15 | criteria provided, single submitter | clinical testing |