ClinVar Genomic variation as it relates to human health

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 68 of the PTEN protein (p.Tyr68Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Cowden syndrome (PMID: 19457929, 21956414, 24778394, 26246517). ClinVar contains an entry for this variant (Variation ID: 233777). 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: 19457929, 26246517). This variant disrupts the p.Tyr68 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9600246, 16704655, 19457929, 20926450, 25669429). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The p.Y68C pathogenic mutation (also known as c.203A>G), located in coding exon 3 of the PTEN gene, results from an A to G substitution at nucleotide position 203. The tyrosine at codon 68 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in numerous individuals with a personal history of Cowden syndrome or Cowden-like disease (Ngeow J, J. et al. Clin. Endocrinol. Metab. 2011 Dec;96(12):E2063-71; Ngeow J et al. J. Clin. Oncol. 2014 Jun;32(17):1818-24; Browning MJ et al. J. Med. Genet. 2015 Aug). Functional analyses in isolated T cells from one affected individual showed reduced PTEN protein expression and increased AKT and S6 phosphorylation in peripheral blood T cells (Browning MJ et al. J. Med. Genet. 2015 Aug). This alteration has also been shown to disrupt function using a humanized yeast model of lipid phosphatase activity in vivo (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955), and demonstrated low intracellular protein abundance on a multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882). In addition, this alteration is located in a putative ATP-biding site, and is associated with an increase in PTEN nuclear localization compared to wildtype controls (Lobo GP et al. Hum. Mol. Genet. 2009 Aug;18(15):2851-62). Further, similar alterations at this codon (p.Y68H, p.Y68S, p.Y68D) have also been reported in individuals with PTEN hamartoma tumor syndrome (PHTS), including a boy with a clinical diagnosis of proteus syndrome and his mother with clinical features of Cowden syndrome (Ambry Internal data, Loffeld A et al. Br. J. Dermatol. 2006;154 (6):1194-8). 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)). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.

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; Published functional studies demonstrate a damaging effect: aberrant phosphatase activity and cellular localization (PMID: 19457929, 29706350); Identified in additional patients with PTEN-related phenotypes referred for genetic testing at GeneDx and in published literature (PMID: 26246517, 24778394); Identified as a de novo variant with confirmed parentage in a patient previously tested at GeneDx and as an apparently de novo variant in multiple patients previously tested at GeneDx and in the published literature with features of PTEN Hamartoma Tumor syndrome (PMID: 29296277); This variant is associated with the following publications: (PMID: 24778394, 26246517, 29785012, 21956414, 19457929, 30287823, 9288766, 25669429, 29296277, 32003824, 30755392, 31594918, 29706350, 24475377)

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29785012, Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19457929, 26246517, 29296277, 32003824].