ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.464A>G (p.Tyr155Cys) (rs1060500126)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000475421 SCV001244247 pathogenic PTEN hamartoma tumor syndrome 2019-11-22 reviewed by expert panel curation PTEN c.464A>G (p.Tyr155Cys) 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). PS3: Phosphatase activity <50% of wild type (PMID 21828076, 10866302, 29706350) PS4: Probands with phenotype specificity score of 4-15.5 (PMID 23399955, internal laboratory contributors SCV000579967.3, ClinVar Organization ID: 19864) PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID: 26957) PM2: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Invitae RCV000475421 SCV000541626 pathogenic PTEN hamartoma tumor syndrome 2020-04-07 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 155 of the PTEN protein (p.Tyr155Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Cowden syndrome or PTEN hamartoma tumor syndrome (PMID: 12614768, 23399955, 17942903, 23335809, 27531073). ClinVar contains an entry for this variant (Variation ID: 404168). This variant has been reported to affect PTEN protein function (PMID: 21828076, 17942903, 10866302). This variant disrupts the p.Tyr155 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (PMID: 30181857), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000491012 SCV000579967 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656112 SCV000598612 uncertain significance Cowden syndrome 1 2017-09-01 criteria provided, single submitter research this variant was indentified in an individual with malformations of cortical development
Ambry Genetics RCV001022838 SCV001184619 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-19 criteria provided, single submitter clinical testing The p.Y155C variant (also known as c.464A>G), located in coding exon 5 of the PTEN gene, results from an A to G substitution at nucleotide position 464. The tyrosine at codon 155 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals meeting at least relaxed Cowden syndrome criteria as well as classic Cowden syndrome criteria (Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Gicquel JJ et al. Am. J. Ophthalmol. 2003 Mar; 135(3):400-2; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; Ngeow J et al. Gastroenterology, 2013 Jun;144:1402-9, 1409.e1-5; Nizialek E et al. Eur. J. Hum. Genet. 2015 Nov;23(11):1538-43; Driessen GJ et al. J. Allergy Clin. Immunol., 2016 12;138:1744-1747.e5; Ambry internal data). In a yeast functional assay, this variant demonstrated loss of in vivo phosphatase activity (Rodr&iacute;guez-Escudero I et al. Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001092596 SCV001249160 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258059 SCV001434890 likely pathogenic PTEN hamartoma tumor syndromes 2019-01-14 criteria provided, single submitter clinical testing The c.464A>G (p.Tyr155Cys) variant in the PTEN gene has been reported in multiple individuals with Cowden's disease or PTEN hamartoma tumor syndrome (PMID 12614768, 17942903, 19265751, 23335809, 23399955, 27531073). This variant is absent from large databases of genetic variation in the general population. In vitro phosphatase activity assay demonstrated that the activity of the mutant protein is equivalent to a null allele (PMID 10866302). Multiple lines of algorithms predict deleterious effect of the p.Tyr155Cys change. Therefore, the c c.464A>G (p.Tyr155Cys) variant in the PTEN gene is classified as likely pathogenic.
University Health Network,Princess Margaret Cancer Centre RCV000475421 SCV001430889 pathogenic PTEN hamartoma tumor syndrome no assertion criteria provided clinical testing This variant c.464 A>G is not present in population databases. It has been reported in individuals affected with PHTS (Bubien 2013, Gicquel 2003, Ngeow 2013, Andres-Pons 2007).

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