ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.822G>A (p.Trp274Ter) (rs587782607)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131976 SCV000187034 pathogenic Hereditary cancer-predisposing syndrome 2020-08-17 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). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507265 SCV000602129 pathogenic not provided 2016-11-11 criteria provided, single submitter clinical testing
GeneDx RCV000507265 SCV000748212 pathogenic not provided 2018-04-19 criteria provided, single submitter clinical testing The W274X variant in the PTEN gene has been reported previously in an individual who had clinical PTEN gene testing; however, additional clinical information was not provided (Pilarski et al., 2011). A different nucleotide substitution (c.821 G>A) resulting in the same amino acid substitution (W274X) has been reported previously as a de novo variant in an individual with features consistent with PTEN hamartoma tumor syndrome (PHTS) (Busa et al., 2014). The W274X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the W274X variant is not observed in large population cohorts (Lek et al., 2016). We interpret W274X as a pathogenic variant, and its presence is consistent with the diagnosis of PHTS in this individual.
Invitae RCV000697400 SCV000826008 pathogenic PTEN hamartoma tumor syndrome 2019-09-27 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. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual referred for PTEN testing who is highly suspicious of having PTEN hamartoma tumor syndrome (PMID: 21659347). ClinVar contains an entry for this variant (Variation ID: 142640). Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). For these reasons, this variant has been classified as Pathogenic.

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