Submissions for variant NM_000314.8(PTEN):c.1027-1G>A

dbSNP: rs1057517809

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000690306	SCV000930125	pathogenic	PTEN hamartoma tumor syndrome	2019-06-25	reviewed by expert panel	curation	PTEN c.1027-1G>A (IVS8-1G>A) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4). PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (Internal laboratory contributor SCV000490754.2)
GeneDx	RCV000414617	SCV000490754	pathogenic	not provided	2019-12-23	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a deletion of the last exon, disrupting the critical C2 domain (Wang 2008); Not observed in large population cohorts (Lek et al., 2016); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Chen 2017); This variant is associated with the following publications: (PMID: 21266528, 27477328, 18626510, 26582918)
Ambry Genetics	RCV000491449	SCV000580074	pathogenic	Hereditary cancer-predisposing syndrome	2016-12-05	criteria provided, single submitter	clinical testing	The c.1027-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 9 of the PTEN gene. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690306	SCV000817988	pathogenic	PTEN hamartoma tumor syndrome	2023-06-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 372482). Disruption of this splice site has been observed in individuals with PTEN-related disease and Cowden syndrome (PMID: 27477328; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 8 of the PTEN gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
Myriad Genetics, Inc.	RCV003449035	SCV004189549	likely pathogenic	Cowden syndrome 1	2023-10-09	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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785587	SCV000924162	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research