Submissions for variant NM_000314.8(PTEN):c.49C>T (p.Gln17Ter)

dbSNP: rs786204910

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204017	SCV000259661	pathogenic	PTEN hamartoma tumor syndrome	2023-02-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln17*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS), collectively also known as PTEN hamartoma tumor syndrome (PMID: 21194675, 21659347, 22266152, 25669429). This variant is also known as PTEN hamartoma tumor syndrome (PMID: 21194675, 21659347, 22266152, 25669429). ClinVar contains an entry for this variant (Variation ID: 189458). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000169851	SCV000277049	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-28	criteria provided, single submitter	clinical testing	The p.Q17* pathogenic mutation (also known as c.49C>T), located in coding exon 1 of the PTEN gene, results from a C to T substitution at nucleotide position 49. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This alteration has been reported in multiple individuals with features of Cowden syndrome/PTEN hamartoma tumor syndrome (Tan MH et al. Am J Hum Genet, 2011 Jan;88:42-56; Heindl M et al. Gastroenterology, 2012 May;142:1093-1096.e6; Nizialek EA et al. Eur J Hum Genet, 2015 Nov;23:1538-43). This variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882). In addition to the clinical data presented in the literature, 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.
Color Diagnostics, LLC DBA Color Health	RCV000169851	SCV000905164	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 1 of the PTEN gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PTEN function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002035	SCV001159859	pathogenic	not specified	2019-03-20	criteria provided, single submitter	clinical testing	The PTEN c.49C>T; p.Gln17Ter variant (rs786204910) is reported in the literature in individuals with PTEN harmartoma tumor syndrome (Heindl 2012, Sarquis 2006, Tan 2011), and is reported as pathogenic in ClinVar (Variation ID: 189458). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Heindl M et al. Autoimmunity, intestinal lymphoid hyperplasia, and defects in mucosal B-cell homeostasis in patients with PTEN hamartoma tumor syndrome. Gastroenterology. 2012 May;142(5):1093-1096.e6. Sarquis MS et al. Distinct expression profiles for PTEN transcript and its splice variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. Am J Hum Genet. 2006 Jul;79(1):23-30. Tan MH et al. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am J Hum Genet. 2011 Jan 7;88(1):42-56.
Myriad Genetics, Inc.	RCV003454440	SCV004188832	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.