ClinVar Genomic variation as it relates to human health

Variant summary: The PTEN c.406T>C (p.Cys136Arg) variant located in the Protein-tyrosine phosphatase-like domain involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 121500 control chromosomes. Multiple publications have cited the variant in affected indivdiuals diagnosed with Cowden Syndrome, BRRS, and PHTS, which was found to cosegregate with disease in multiple families. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Functional studies have demonstrated an impact of this variant on protein stability leading to increased proteasome activity which has been reported as a hallmark of human cancers. Taken together, this variant is classified as pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with ­hamartoma tumour syndrome (MONDO#0017623). Loss of function is the mechanism for null variants while missense variants have been demonstrated to exert either a loss of function or dominant-negative mechanism (GeneReviews). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In particular, PTEN-related Proteus syndrome has been described to be a highly variable disorder (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in multiple unrelated individuals or families with PTEN hamartoma tumour syndrome (ClinVar; PMIDs: 10848731, 17941496, 21343951, 23886400, 35227301). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by segregation testing). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 136 of the PTEN protein (p.Cys136Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Cowden syndrome (PMID: 10848731, 20600018, 21343951, 21659347, 22520842, 23335809, 23886400, 24778394). ClinVar contains an entry for this variant (Variation ID: 183726). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTEN protein function. Experimental studies have shown that this missense change affects PTEN function (PMID: 23475934). For these reasons, this variant has been classified as Pathogenic.

The p.C136R pathogenic mutation (also known as c.406T>C), located in coding exon 5 of the PTEN gene, results from a T to C substitution at nucleotide position 406. The cysteine at codon 136 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration was described as a de novo mutation in a Japanese patient with Cowden disease (Kubo Y et al. Br. J. Dermatol. 2000 Jun;142(6):1100-5). In one PTEN Hamartoma Tumor Syndrome (PHTS) family, this mutation segregated with disease in a mother and her two daughters. Clinical features included macrocephaly and thyroid lesions (follicular carcinoma and adenoma) in all three individuals, breast cancer in the mother, vertebral hemangioma in one daughter, and cortical dysplasia in the other daughter (Jenny B et al. J. Neurosurg. 2007 Oct;107(4 Suppl):307-13; Venturini G et al. Ophthalmology 2012 Apr;119(4):857-64). This mutation has also been observed in other individuals with PHTS (Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; Galatola M et al. BMC Med. Genet., 2012 Apr;13:28) including those with neurological features of PHTS such as autism and developmental delay (He X et al. Cancer Res. 2013 May;73(10):3029-40). 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.

Published functional studies demonstrate a damaging effect: impaired phosphatase activity, reduced PTEN protein levels and stability (He et al., 2013; Mighell et al., 2018; Matreyek et al., 2018); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21659347, 31965297, 28380455, 29663862, 23335809, 32601921, 17941496, 22281088, 10848731, 27148581, 25461771, 23886400, 22520842, 15211648, 18558293, 23475934, 21343951, 20600018, 24778394, 21194675, 26376867, 31006514, 29785012, 19457929, 24475377, 29706350, 30787465, 32003824)

The PTEN c.925T>C (p.Cys309Arg) variant (also known as c.406T>C) has been reported in individuals affected with Cowden syndrome (Kubo Y et al., 2000). Experimental studies demonstrate a damaging effect: impaired phosphatase activity, reduced PTEN protein levels and stability (He X et al., 2013). The p.Cys309Arg variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Cys at position 309 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Cys309Arg in PTEN is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23475934, 10866302]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9735393, 10848731, 16773562, 21343951, 23475934].

This missense variant replaces cysteine with arginine at codon 136 of the PTEN protein. Functional studies have shown that this variant reduces protein stability and activity (PMID: 23475934, 29663862). This variant has been reported in individuals affected with Cowden syndrome/PTEN hamartoma tumour syndrome (PMID: 10848731, 20600018, 21194675, 21343951, 23335809, 23475934, 24778394, 25669429, 23886400, 26376867). It has been shown that this variant segregates with disease (PMID: 23886400). 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. Based on the available evidence, this variant is classified as Pathogenic.