Submissions for variant NM_000314.8(PTEN):c.80A>C (p.Tyr27Ser)

dbSNP: rs886041877

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV001855073	SCV004183302	likely pathogenic	PTEN hamartoma tumor syndrome	2023-08-04	reviewed by expert panel	curation	NM_000314.8(PTEN):c.80A>C (p.Tyr27Ser) 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 3.0.0). 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)] PS3_P: Other studies demonstrating lipid phosphatase activity <50% of wild-type or abnormal in vitro cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3_moderate. Hans, et al. PMID: 10866302: demonstrated low phosphatase activity. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. [internal laboratory contributor(s)] PM2_P: Absent in large sequenced populations OR 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. PP3: in silico REVEL score of 0.966 (>0.7)
GeneDx	RCV000355517	SCV000330664	pathogenic	not provided	2016-07-06	criteria provided, single submitter	clinical testing	The Y27S pathogenic variant in the PTEN gene has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in a glioblastoma tumor sample (Davies et al., 1999). Functional studies demonstrate that the Y27S variant, located in the PTEN phosphatase domain, inactivates protein phosphatase activity (Han et al., 2000). The Y27S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y27S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Several missense variants in the same residue (Y27N, Y27C) and nearby residues (D22G, L23V, D24H, D24G, D24Y, D24V, L25F, T26P, T26I, P30L, I32N) have been reported in the Human Gene Mutation Database in association with PTEN-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret Y27S as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855073	SCV002172915	uncertain significance	PTEN hamartoma tumor syndrome	2021-06-17	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 280724). 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. This variant disrupts the p.Tyr27 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24375884, 32350270). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PTEN protein function (PMID: 10866302, 29785012, 29706350). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with serine at codon 27 of the PTEN protein (p.Tyr27Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine.
Ambry Genetics	RCV002418104	SCV002677113	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-05	criteria provided, single submitter	clinical testing	The p.Y27S pathogenic mutation (also known as c.80A>C) is located in coding exon 2 of the PTEN gene. The tyrosine at codon 27 is replaced by serine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 2. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with PTEN hamartoma tumor syndrome (external laboratory communication). In a functional assay using a bacterial model, p.Y27S demonstrated reduced lipid phosphatase activity compared to wild-type PTEN; however, in a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for p.Y27S variant was functionally inconclusive (Han SY et al. Cancer Res, 2000 Jun;60:3147-51; Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003454785	SCV004188794	likely pathogenic	Cowden syndrome 1	2023-09-26	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 10866302, 29785012].