Submissions for variant NM_000314.8(PTEN):c.1171C>T (p.Pro391Ser)

gnomAD frequency: 0.00001  dbSNP: rs786203911

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000538790	SCV000840495	uncertain significance	PTEN hamartoma tumor syndrome	2020-03-23	reviewed by expert panel	curation	PTEN c.1171C>T (p.Pro391Ser) PTEN c.1171C>T (p.Pro391Ser) is currently classified as a variant of uncertain significance 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). PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (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. BS3: Missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. (PMID 30993208, 29785012, 29706350)
Ambry Genetics	RCV000167422	SCV000218278	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-20	criteria provided, single submitter	clinical testing	The p.P391S variant (also known as c.1171C>T), located in coding exon 9 of the PTEN gene, results from a C to T substitution at nucleotide position 1171. The proline at codon 391 is replaced by serine, an amino acid with similar properties. This alteration was identified once in a large cohort of individuals diagnosed with autism spectrum disorder who underwent whole exome sequencing (Saskin A et al. J. Hum. Genet., 2017 Jun;62:657-659). This variant demonstrated possibly wildtype-like abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally neutral (Mighell TL et al. Am. J. Hum. Genet. 2018 05;102:943-955). In another functional study, this variant demonstrated PIP3 phosphatase activity and subcellular localization similar to PTEN wildtype (Mingo J et al. NPJ Precis Oncol, 2019 Apr;3:11). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000212888	SCV000222170	uncertain significance	not specified	2017-05-05	criteria provided, single submitter	clinical testing	This variant is denoted PTEN c.1171C>T at the cDNA level, p.Pro391Ser (P391S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PTEN Pro391Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PTEN Pro391Ser occurs at a position that is conserved across species and is not located in a known functional domain (Nguyen 2014, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PTEN Pro391Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Eurofins Ntd Llc (ga)	RCV000585009	SCV000232946	uncertain significance	not provided	2015-04-17	criteria provided, single submitter	clinical testing
Invitae	RCV000538790	SCV000645550	uncertain significance	PTEN hamartoma tumor syndrome	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 391 of the PTEN protein (p.Pro391Ser). This variant is present in population databases (rs786203911, gnomAD 0.0009%). 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: 187673). 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 95%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 29706350, 29785012, 30993208). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000585009	SCV000692694	uncertain significance	not provided	2017-07-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462242	SCV004206669	uncertain significance	Glioma susceptibility 2	2023-09-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167422	SCV004357079	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 391 of the PTEN protein. Functional studies have reported this variant does not significantly affect PTEN protein function (PMID: 29706350). This variant has been reported in an individual affected with cancer (PMID: 35089076). This variant has been identified in 2/243908 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV000538790	SCV004838613	uncertain significance	PTEN hamartoma tumor syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 391 of the PTEN protein. Functional studies have reported this variant does not significantly affect PTEN protein function (PMID: 29706350). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/243908 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.