Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000588249 | SCV000696520 | uncertain significance | not provided | 2017-07-06 | criteria provided, single submitter | clinical testing | Variant summary: The PTEN c.1021T>G (p.Phe341Val) variant involves the alteration of a conserved nucleotide located in the C2 domain. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 120464 control chromosomes. While the variant has been reported as a somatic mutation in various tumor types in the literature, it has not, to our knowledge, been reported as a germline mutation in affected invidivuals via publications, databases, or clinical labs. Functional studies show the variant to alter phosphoinositol phosphatase activity, show reduced activity in a yeast based-transactivation assay, and result in the complete loss of binding to PICT-1 (Han_2010, Kato_2000, Okahara_2004). Additionally, a knockout mouse model harboring this variant showed heterozygous mice develop carcinoma in the thymus, stomach, adrenal medulla, and mammary gland but not in other organs typically sensitive to Pten deficiency including the thyroid, prostate and uterus (Castera_2015). Although the study did not provide any primary evidence supporting the loss or lack thereof of the phosphatase activity on tissue homogenates, based on the viability of knock out embryos in the absence of overt AKT activation, the authors postulated that this missense variant (p.F341V) disrupts a function that is distinct from the well-established lipid phosphatase function of PTEN. Therefore, the effect of this variant on the established role of PTEN as a tumor suppressor through its lipid phosphatase activity leading to a negative regulation of the PI3K/Akt pathway is not clearly established. Furthermore, to our knowledge, functional assays reproducing the altered phosphatase activity on patient tissue or mammalian models have not been reported at the time of this review. In the absence of clinical information, the variant is classified as a variant of uncertain significance-possibly pathogenic until additional information becomes available. |
| Myriad Genetics, |
RCV003451331 | SCV004189545 | likely pathogenic | Cowden syndrome 1 | 2023-10-09 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 26302789]. |