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	2014-02-21	criteria provided, single submitter	clinical testing	Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
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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