Submissions for variant NM_000314.8(PTEN):c.287C>T (p.Pro96Leu)

dbSNP: rs1554898074

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000807643	SCV001335270	likely pathogenic	PTEN hamartoma tumor syndrome	2024-04-05	reviewed by expert panel	curation	PTEN c.287C>T (p.Pro96Leu) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). PS3_Moderate: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -2.48 (<= -1.11) on a high throughput phosphatase assay (PMID 29706350). PM2_Supporting: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history (internal laboratory contributor SCV000616840.3). 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 > 0.7 (score of this variant =0.933).
GeneDx	RCV000522760	SCV000616840	pathogenic	not provided	2024-11-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: impaired lipid phosphatase activity (PMID: 29706350); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9331072, 18772396, 25256166, 24475377, 29785012, 32442409, 29706350)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000807643	SCV000947708	likely pathogenic	PTEN hamartoma tumor syndrome	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 96 of the PTEN protein (p.Pro96Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 449089). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 29706350). This variant disrupts the p.Pro96 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11918710, 17942903, 21828076; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics	RCV002438251	SCV002751253	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-04-08	criteria provided, single submitter	clinical testing	The p.P96L variant (also known as c.287C>T), located in coding exon 5 of the PTEN gene, results from a C to T substitution at nucleotide position 287. The proline at codon 96 is replaced by leucine, an amino acid with similar properties. In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am. J. Hum. Genet. 2018 05;102:943-955). Based on internal structural analysis, the p.P96L alteration demonstrated disruption to the PTEN phosphatase domain (Ambry internal data; Lee CU et al. Angew Chem Int Ed Engl, 2015 Nov;54:13796-800; Dempsey DR et al. Nat Struct Mol Biol, 2021 10;28:858-868). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000522760	SCV005624701	likely pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing	The PTEN c.287C>T (p.Pro96Leu) variant has been reported to have a deleterious effect on PTEN protein function (PMID: 29706350 (2018)). In addition, a different variant located at the same position (PTEN c.287C>A (p.Pro96Gln)) has been reported to partial PTEN protein activity and expression (PMID: 17942903 (2007)) and has been reported in an individual with Cowden Syndrome (PMID: 11918710 (2002)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.