Submissions for variant NM_000314.8(PTEN):c.302T>A (p.Ile101Asn)

dbSNP: rs1339631701

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000803332	SCV000943196	likely pathogenic	PTEN hamartoma tumor syndrome	2023-03-23	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 648578). 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. This variant disrupts the p.Ile101 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21194675, 21659347, 24375884, 27531073, 29608813, 29706350). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PTEN function (PMID: 29706350). 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. This variant has not been reported in the literature in individuals affected with PTEN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 101 of the PTEN protein (p.Ile101Asn).
GeneDx	RCV002464324	SCV002759168	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24475377)
Ambry Genetics	RCV003353034	SCV004051992	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-07	criteria provided, single submitter	clinical testing	The p.I101N variant (also known as c.302T>A), located in coding exon 5 of the PTEN gene, results from a T to A substitution at nucleotide position 302. The isoleucine at codon 101 is replaced by asparagine, an amino acid with dissimilar properties. In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). Based on internal structural analysis, the p.I101N variant is mildly destabilizing to the local structure and it is more destabilizing than several nearby pathogenic variants (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.