Submissions for variant NM_000314.8(PTEN):c.542T>C (p.Leu181Pro)

dbSNP: rs1589659492

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV001213247	SCV002576559	pathogenic	PTEN hamartoma tumor syndrome	2021-06-04	reviewed by expert panel	curation	PTEN c.542T>C (p.Leu181Pro) meets criteria to be classified as 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) SCV001524663.1) PS3: Phosphatase activity <50% (PMID 29706350, PMID 21828076) PM2: 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 17526801, internal laboratory contributor(s) SCV000579246.1)
Ambry Genetics	RCV001024095	SCV001186053	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-07	criteria provided, single submitter	clinical testing	The p.L181P pathogenic mutation (also known as c.542T>C), located in coding exon 6 of the PTEN gene, results from a T to C substitution at nucleotide position 542. The leucine at codon 181 is replaced by proline, an amino acid with similar properties. This variant has been detected in cohorts of patients meeting either clinical diagnostic criteria for Cowden syndrome (CS), relaxed clinical diagnostic criteria for CS-like, or were suspected of having CS (Heald B et al. Gastroenterology 2010 Dec;139:1927-33; Tan MH et al. Am. J. Hum. Genet., 2011 Jan;88:42-56; Rodr&iacute;guez-Escudero I et al. Hum. Mol. Genet. 2011 Nov;20:4132-42; Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23:1538-43; Pilarski R et al. J Med Genet, 2011 Aug;48:505-12). This alteration was reported in a pediatric patient with macrocephaly and a vascular anomaly (Tan WH et al. J. Med. Genet. 2007 Sep;44:594-602). This alteration was also reported as a de novo occurrence in an individual with clinical features of PTEN hamartoma tumor syndrome (Personal communication with the ClinGen PTEN VCEP). The p.L181P variant demonstrated deficient PTEN activity in an in vivo functional assay performed in yeast (Rodr&iacute;guez-Escudero I et al. Hum. Mol. Genet. 2011 Nov;20:4132-42). This alteration has also been shown to disrupt function using a humanized yeast model of lipid phosphatase activity in vivo (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). 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. 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)). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001213247	SCV001384869	pathogenic	PTEN hamartoma tumor syndrome	2023-05-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PTEN function (PMID: 21828076, 29706350). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PTEN protein function. ClinVar contains an entry for this variant (Variation ID: 825730). This missense change has been observed in individual(s) with clinical features of PTEN hamartoma tumor syndrome (PMID: 17526801, 20600018, 21659347; external communication). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 181 of the PTEN protein (p.Leu181Pro).
Baylor Genetics	RCV001332361	SCV001524663	pathogenic	Macrocephaly-autism syndrome	2019-08-29	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Myriad Genetics, Inc.	RCV003455127	SCV004188740	likely pathogenic	Cowden syndrome 1	2023-09-28	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 32442409, 17526801, 21659347]. This variant is expected to disrupt protein structure [Myriad internal data].