Submissions for variant NM_000314.8(PTEN):c.802-1G>A

dbSNP: rs1257124719

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Johns Hopkins Genomics, Johns Hopkins University	RCV000850161	SCV000992351	likely pathogenic	Macrocephaly-autism syndrome	2019-04-23	criteria provided, single submitter	clinical testing	This PTEN variant is absent from large population datasets and has not been reported in the literature, to our knowledge. Bioinformatic analysis predicts that this variant would affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. At this time, c.802-1G>A is considered likely pathogenic.
Invitae	RCV001211799	SCV001383357	pathogenic	PTEN hamartoma tumor syndrome	2021-07-09	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 7 of the PTEN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals affected with Cowden syndrome (PMID: 27477328, 28677221). ClinVar contains an entry for this variant (Variation ID: 689447). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001572487	SCV001797140	pathogenic	not provided	2021-05-17	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV003169079	SCV003855240	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-02-13	criteria provided, single submitter	clinical testing	The c.802-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 8 of the PTEN gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003453773	SCV004189513	likely pathogenic	Cowden syndrome 1	2023-10-02	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.