Submissions for variant NM_000314.8(PTEN):c.492+1G>A

dbSNP: rs1554898242

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001585039	SCV001811198	pathogenic	not provided	2021-01-12	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29484624)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001882705	SCV002315485	likely pathogenic	PTEN hamartoma tumor syndrome	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the PTEN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of PTEN hamartoma tumor syndrome (PMID: 33876391, 34906515, 35227301). ClinVar contains an entry for this variant (Variation ID: 1212448). Studies have shown that disruption of this splice site results in activation of cryptic splice sites and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002241380	SCV002511475	likely pathogenic	Cowden syndrome	2022-04-16	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.492+1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250786 control chromosomes. c.492+1G>A has been reported in the literature as a de-novo variant in at-least one individual with PTEN hamartoma tumor syndrome who presented with hypoglycemia and macrocephaly (example, Maines_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002343756	SCV002646395	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-07-24	criteria provided, single submitter	clinical testing	The c.492+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the PTEN gene. This variant has been identified as a de novo occurrence twice in unrelated individuals with features of PTEN hamartoma tumor syndrome (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (personal communication). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Revvity Omics, Revvity	RCV001585039	SCV003826704	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003451820	SCV004188724	likely pathogenic	Cowden syndrome 1	2023-09-28	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. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 28677221]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 33887726, 33876391, 28677221, 24345843, 32196895, 21659347].
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV001585039	SCV001934215	not provided	not provided		no assertion provided	research