Submissions for variant NM_000314.8(PTEN):c.59G>T (p.Gly20Val)

dbSNP: rs1064795967

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV001221711	SCV004183304	likely pathogenic	PTEN hamartoma tumor syndrome	2023-08-04	reviewed by expert panel	curation	NM_000314.8(PTEN):c.59G>T (p.Gly20Val) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history (Internal laboratory contributor(s) SCV001393771.3). PS4_P: Proband(s) with phenotype specificity score of 1-1.5 Internal laboratory contributor(s) SCV001393771.3). PM2_Supporting: Absent in large sequenced populations (PMID 27535533). 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. PP3: REVEL score = 0.931.
Ambry Genetics	RCV000490850	SCV000580061	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-25	criteria provided, single submitter	clinical testing	The p.G20V variant (also known as c.59G>T), located in coding exon 1 of the PTEN gene, results from a G to T substitution at nucleotide position 59. The glycine at codon 20 is replaced by valine, an amino acid with dissimilar properties. In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was wild-type-like (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). This variant demonstrated wild-type-like intracellular protein abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001221711	SCV001393771	likely pathogenic	PTEN hamartoma tumor syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 20 of the PTEN protein (p.Gly20Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with features consistent with a PTEN-related condition (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 428266). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt PTEN function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 29706350, 29785012). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV003441894	SCV004168195	uncertain significance	not provided	2023-04-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24475377)