Submissions for variant NM_000314.8(PTEN):c.822G>A (p.Trp274Ter)

dbSNP: rs587782607

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131976	SCV000187034	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-30	criteria provided, single submitter	clinical testing	The p.W274* pathogenic mutation (also known as c.822G>A) located in coding exon 8 of the PTEN gene, results from a G to A substitution at nucleotide position 822. This changes the amino acid from a tryptophan to a stop codon within coding exon 8. This alteration and a separate nucleotide change (c.821G>A) resulting in protein truncation at the same position have both been identified in patients with features consistent with PTEN hamartoma tumor syndrome (PHTS) (Pilarski R et al. J. Med. Genet. 2011; 48:505-12; Pilarksi R, personal communication; Busa T et al. Eur. J. Paediatr. Neurol. 2015 Mar;19:188-92; Ambry internal data). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507265	SCV000602129	pathogenic	not provided	2023-12-06	criteria provided, single submitter	clinical testing	The PTEN c.822G>A (p.Trp274*) variant causes the premature termination of PTEN protein synthesis. This variant has been reported in the published literature in an individual with clinical features suggestive of PTEN hamartoma tumor syndrome (PHTS) (PMID: 21659347 (2011)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
GeneDx	RCV000507265	SCV000748212	pathogenic	not provided	2024-08-22	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25737639, 21659347, 28152038, 25549896)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697400	SCV000826008	pathogenic	PTEN hamartoma tumor syndrome	2024-05-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp274*) 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 PTEN hamartoma tumor syndrome (PMID: 21659347). ClinVar contains an entry for this variant (Variation ID: 142640). For these reasons, this variant has been classified as Pathogenic.
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV002055846	SCV002320789	pathogenic	Cowden syndrome 1	2022-01-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528860	SCV004104337	pathogenic	PTEN-related disorder	2023-09-20	criteria provided, single submitter	clinical testing	The PTEN c.822G>A variant is predicted to result in premature protein termination (p.Trp274*). This variant has been reported in individuals with PTEN hamartoma tumor syndrome (Pilarski et al. 2011. PubMed ID: 21659347; LaDuca et al. 2017. PubMed ID: 28152038). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in PTEN are expected to be pathogenic. This variant is interpreted as pathogenic.
Myriad Genetics, Inc.	RCV002055846	SCV004189561	pathogenic	Cowden syndrome 1	2023-10-02	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.