Submissions for variant NM_000314.8(PTEN):c.331T>C (p.Trp111Arg)

dbSNP: rs398123321

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000758231	SCV000886868	likely pathogenic	PTEN hamartoma tumor syndrome	2021-06-04	reviewed by expert panel	curation	PTEN c.331T>C (p.Trp111Arg) 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). PS3: Phosphatase activity <50% of wild type (PMID 29785012, 29706350) PM2: Absent in large sequenced populations (PMID 27535533). PS4_M: Probands with phenotype specificity score of 2-3.5. (internal laboratory contributor(s) ClinVar Organization ID: 61756, ClinVar Organization ID: 19864) 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.
Eurofins Ntd Llc (ga)	RCV000078613	SCV000110469	likely pathogenic	not provided	2012-07-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758231	SCV001225621	pathogenic	PTEN hamartoma tumor syndrome	2024-07-16	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 111 of the PTEN protein (p.Trp111Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PTEN-related conditions (PMID: 1147684, 35102303; Invitae). ClinVar contains an entry for this variant (Variation ID: 92820). 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, 29785012). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000078613	SCV002008213	pathogenic	not provided	2022-09-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: significantly reduced 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; Observed in an individual with features overlapping Proteus syndrome and PTEN Hamartoma Tumor syndrome in published literature, and also observed in patients with a personal history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx (Zhou et al., 2001); This variant is associated with the following publications: (PMID: 23757202, 16704655, 12938083, 12471211, 29785012, 29706350, 29416795, 11476841, 24475377)
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV001807780	SCV002058106	likely pathogenic	Cowden syndrome 1	2022-01-13	criteria provided, single submitter	clinical testing	PTEN c.331T>C variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome (PHTS) with an autosomal dominant inheritance, following ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2 (https://www.clinicalgenome.org/affiliation/50012). Published functional assays have demonstrated that this variant significantly compromises the phosphatase activity of PTEN (PMID 29785012; 29706350) (PS3). This substitution is absent in large-scale general population reference sequencing datasets (PMID 32461654) (PM2). PTEN is defined by the PTEN Expert Panel as a gene with a low rate of benign missense variation, in which missense variants are a common mechanism of disease (PP2). In silico tools support that this missense variant has a deleterious effect (PP3). This variant was identified in a patient from our unit who met the consensus clinical diagnostic criteria for an operational diagnosis of Cowden syndrome (PMID 24136893; Rofes et al. 2022, submitted manuscript). The Cleveland Clinic (CC) score in this patient was >30 (PMID 21194675) (PS4_Supporting). In addition, this variant was previously reported in an individual diagnosed with Proteus syndrome, a genetic condition that also belongs to PHTS spectrum (PMID 11476841).
Ambry Genetics	RCV002321573	SCV002606208	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-11	criteria provided, single submitter	clinical testing	The p.W111R pathogenic mutation (also known as c.331T>C), located in coding exon 5 of the PTEN gene, results from a T to C substitution at nucleotide position 331. The tryptophan at codon 111 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified in an individual who met clinical diagnostic criteria for PTEN hamartoma tumor syndrome (Ambry internal data). This variant was also identified in a patient with Proteus syndrome, but no details on clinical features were reported (Zhou X et al. Lancet, 2001 Jul;358:210-1). In a high-throughput assay measuring lipid phosphatase activity, this variant demonstrated deficient function (Mighell TL et al. Am. J. Hum. Genet., 2018 05;102:943-955). In another high-throughput assay measuring intracellular protein abundance, this variant demonstrated low protein abundance (Matreyek KA et al. Nat. Genet., 2018 06;50:874-882). Based on an internal structural analysis using published crystal structures, this variant is moderately destabilizing to the structure of the phosphatase catalytic domain of PTEN (Ambry internal data; Georgescu MM et al. Cancer Res., 2000 Dec;60:7033-8; Lee CU et al. Angew. Chem. Int. Ed. Engl., 2015 Nov;54:13796-800). This variant was not reported in population-based 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.