Submissions for variant NM_000314.8(PTEN):c.302T>C (p.Ile101Thr)

dbSNP: rs1339631701

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001018187	SCV001179386	pathogenic	Hereditary cancer-predisposing syndrome	2018-09-14	criteria provided, single submitter	clinical testing	The p.I101T pathogenic mutation (also known as c.302T>C), located in coding exon 5 of the PTEN gene, results from a T to C substitution at nucleotide position 302. The isoleucine at codon 101 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. This variant has been detected in patients who met clinical diagnostic criteria for Cowden syndrome (CS) or relaxed International Cowden Consortium operational criteria for CS like (Tan MH et al. Am. J. Hum. Genet. 2011 Jan;88:42-56; Vanderver A et al. Am. J. Med. Genet. A. 2014 Mar;164A:627-33; Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23:1538-43; Driessen GJ et al. J. Allergy Clin. Immunol. 2016 12;138:1744-1747.e5; Plamper M et al. Eur. J. Pediatr. 2018 Mar;177:429-435; Wong CW et al. Autism Res. 2018 Apr;[Epub ahead of print]). Additionally, this variant has been found de novo in multiple unrelated patients (Vanderver A et al. Am. J. Med. Genet. A. 2014 Mar;164A:627-33; Driessen GJ et al. J. Allergy Clin. Immunol. 2016 12;138:1744-1747.e5; Wong CW et al. Autism Res. 2018 Apr;[Epub ahead of print]). In a functional study, this alteration demonstrated a reduction in lipid phosphatase activity, protein expression, and nuclear localization (Wong CW et al. Autism Res. 2018 Apr;[Epub ahead of print]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001055467	SCV001219860	pathogenic	PTEN hamartoma tumor syndrome	2023-08-10	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 101 of the PTEN protein (p.Ile101Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of PTEN-related conditions (PMID: 21194675, 21659347, 24375884, 27531073, 29608813, 35227301; Invitae). ClinVar contains an entry for this variant (Variation ID: 822660). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function. Experimental studies have shown that this missense change affects PTEN function (PMID: 29608813, 29706350). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001547112	SCV001766742	pathogenic	not provided	2021-12-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: decreased phosphatase activity and protein expression (Mighell et al., 2018; Wong et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29608813, 27324988, 27514801, 21194675, 27531073, 17351349, 26354773, 31336731, 31006514, 29663862, 30528446, 29706350, 24375884, 24475377, 32350270, 31981491)
3billion	RCV003152744	SCV003841889	likely pathogenic	Cowden syndrome 1	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000822660). A different missense change at the same codon (p.Ile101Phe) has been reported to be associated with PTEN related disorder (PMID: 26633542). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Myriad Genetics, Inc.	RCV003152744	SCV004188725	likely pathogenic	Cowden syndrome 1	2023-09-27	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 29608813, 27531073, 24375884, 29273943]. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 32350270].
Baylor Genetics	RCV003461368	SCV004204847	pathogenic	Glioma susceptibility 2	2022-11-28	criteria provided, single submitter	clinical testing
GenomeConnect - Brain Gene Registry	RCV003987762	SCV004804594	not provided	Macrocephaly-autism syndrome; Bannayan-Riley-Ruvalcaba syndrome; PTEN hamartoma tumor syndrome		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 07-23-2022 by GeneDx. 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 Dr. Philip Payne 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/.