Submissions for variant NM_000314.8(PTEN):c.113C>T (p.Pro38Leu)

dbSNP: rs1064796886

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV003455067	SCV004183294	pathogenic	PTEN hamartoma tumor syndrome	2023-10-11	reviewed by expert panel	curation	NM_000314.8(PTEN):c.113C>T (p.Pro38Leu) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2_VS: Two proven de novo observations in a patient with the disease and no family history. (internal laboratory contributor: SCV002757182.1). PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -3.772 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor: SCV002757182.1). 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. PP3: REVEL score > 0.7 (score of this variant = 0.923)
Ambry Genetics	RCV001009991	SCV001170130	uncertain significance	Hereditary cancer-predisposing syndrome	2018-02-22	criteria provided, single submitter	clinical testing	The p.P38L variant (also known as c.113C>T), located in coding exon 2 of the PTEN gene, results from a C to T substitution at nucleotide position 113. The proline at codon 38 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). 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.
GeneDx	RCV002462255	SCV002757182	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: significantly reduced lipid phosphatase activity (Mighell et al., 2018); 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; This variant is associated with the following publications: (PMID: 24475377, 29706350, 27535533)