Submissions for variant NM_000314.8(PTEN):c.48T>G (p.Tyr16Ter)

dbSNP: rs587782187

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000645066	SCV000766807	pathogenic	PTEN hamartoma tumor syndrome	2023-06-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 536556). A different variant (c.48T>A) giving rise to the same protein effect has been determined to be pathogenic (PMID: 16773562, 21194675). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr16*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000645066	SCV000967758	pathogenic	PTEN hamartoma tumor syndrome	2023-02-02	criteria provided, single submitter	clinical testing	The p.Tyr16X variant in PTEN has been reported as a consequence of at least 4 different cDNA changes and is present in ClinVar (c.48T>G, c.48T>A: ID# 142027, c.48_49delinsAT, or c.47dupA: ID# 234409). The c.48T>G variant, identified in this individual, has not been previously reported in individuals with PTEN hamartoma tumor syndrome (PHTS), but the available data from the other changes supports pathogenicity: Collectively, the p.Tyr16X variant has been reported in at least 6 individuals with phenotypes consistent PTEN hamartoma tumor syndrome (c.48T>A: 2 individuals with Cowden syndrome (SC) (Tan 2011); c.48_49delinsAT: 1 individual with CS and 1 individual with Bannayan-Riley-Ruvalcaba syndrome (BRRS) (Sarquis 2006); c.47dupA: 1 individual with CS or CS-like syndrome with hyperplastic polyps in the upper gastrointestinal tract (Zbuk 2007, Ngeow 2011, Head 2010); p.Tyr16X (cDNA change unspecified: 1 individual with adult Lhermitte-Duclos disease (LDD) and clinical features of Cowden (Zhou 2003)). All changes leading to the pTyr16X variant are absent from large population studies. This variant represents a premature termination codon at position 16, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PTEN gene is an established disease mechanism in PTEN hamartoma tumor syndrome. In summary, the p.Tyr16X variant meets criteria to be classified as pathogenic for PTEN hamartoma tumor syndrome in an autosomal dominant manner based upon absence from controls, predicted impact on the protein, and presence in affected individuals. ACMG/AMP Criteria applied: PVS1, PM2, PS4_moderate.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001195980	SCV001366407	pathogenic	Familial meningioma	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4,PP5.
Centogene AG - the Rare Disease Company	RCV001809711	SCV002059853	pathogenic	Cowden syndrome 1	2021-02-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002334144	SCV002638954	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-21	criteria provided, single submitter	clinical testing	The p.Y16* pathogenic mutation (also known as c.48T>G), located in coding exon 1 of the PTEN gene, results from a T to G substitution at nucleotide position 48. This changes the amino acid from a tyrosine to a stop codon within coding exon 1. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV001809711	SCV004188850	pathogenic	Cowden syndrome 1	2023-09-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Yale Center for Mendelian Genomics, Yale University	RCV000645066	SCV002106932	pathogenic	PTEN hamartoma tumor syndrome	2020-10-19	no assertion criteria provided	literature only