ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.685T>A (p.Ser229Thr)

dbSNP: rs587781998
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clingen PTEN Variant Curation Expert Panel, Clingen RCV000696843 SCV001335271 uncertain significance PTEN hamartoma tumor syndrome 2020-03-23 reviewed by expert panel curation PTEN c.685T>A (p.Ser229Thr) is currently classified as a variant of uncertain significance 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). PM2: Absent in large sequenced populations 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 BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350)
Ambry Genetics RCV000130411 SCV000185273 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-19 criteria provided, single submitter clinical testing The p.S229T variant (also known as c.685T>A), located in coding exon 7 of the PTEN gene, results from a T to A substitution at nucleotide position 685. The serine at codon 229 is replaced by threonine, an amino acid with similar properties. This variant has been detected in multiple individuals with no reported features of PTEN-associated disease (Ambry internal data). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally wild-type-like (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Eurofins Ntd Llc (ga) RCV000179748 SCV000232047 uncertain significance not provided 2015-04-17 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000660236 SCV000782242 uncertain significance Cowden syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000696843 SCV000825422 uncertain significance PTEN hamartoma tumor syndrome 2023-12-10 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 229 of the PTEN protein (p.Ser229Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 141771). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt PTEN function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 29706350, 32350270). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000179748 SCV000889805 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing
GeneDx RCV000179748 SCV001793897 uncertain significance not provided 2020-03-11 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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