Submissions for variant NM_000314.8(PTEN):c.165-1G>C

dbSNP: rs786203847

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV001172259	SCV001335266	pathogenic	PTEN hamartoma tumor syndrome	2020-03-23	reviewed by expert panel	curation	PTEN c.165-1G>C (IVS2-1G>C) 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 PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 28677221)
Color Diagnostics, LLC DBA Color Health	RCV001525989	SCV001736228	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-06-25	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the canonical -1 position of intron 2 splice acceptor site of the PTEN gene. An RNA study has reported that this variant causes skipping of exon 3, resulting in p.Arg55Ser and p.Phe56_Leu70del change at the protein level (PMID: 28677221). Multiple pathogenic variants are reported in the affected region (Clinvar), indicating that this variant affects functionally important region of the PTEN gene. This variant has been reported in an individual showing features of Cowden syndrome, such as macrocephaly, Hamartomatous intestinal polyps, lipomas and thyroid lesions (PMID: 28677221). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PTEN function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV001525989	SCV002703487	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-12-02	criteria provided, single submitter	clinical testing	The c.165-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 3 of the PTEN gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). In one study, RT-PCR analysis using mRNA derived from a patient with clinical features of PTEN hamartoma tumor syndrome demonstrated this variant was associated with exon 3 skipping (Chen HJ et al. Hum Mutat, 2017 10;38:1372-1377). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV003311827	SCV004009998	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	PTEN: PVS1, PM2, PS3:Supporting
Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute	RCV000516009	SCV000579224	pathogenic	Cowden syndrome 1	2017-05-26	no assertion criteria provided	research
GenomeConnect - Brain Gene Registry	RCV001172259	SCV002104232	not provided	PTEN hamartoma tumor syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 12/09/2015 by lab or GTR ID 25969. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV003492075	SCV004240772	pathogenic	Cowden syndrome		no assertion criteria provided	clinical testing