ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.80A>G (p.Tyr27Cys) (rs886041877)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000471888 SCV001244234 likely pathogenic PTEN hamartoma tumor syndrome 2019-11-22 reviewed by expert panel curation PTEN c.80A>G (p.Tyr27Cys) meets criteria to be classified as likely 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). PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 24375884) 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 24375884)
Invitae RCV000471888 SCV000541611 uncertain significance PTEN hamartoma tumor syndrome 2016-11-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 27 of the PTEN protein (p.Tyr27Cys). 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 shown to arise de novo in an individuals affected with PTEN hamartoma tumor syndrome (PHTS) (PMID: 24375884). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on mRNA splicing and protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000622559 SCV000742253 likely pathogenic Inborn genetic diseases 2017-04-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV001027175 SCV001189689 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-16 criteria provided, single submitter clinical testing The p.Y27C variant (also known as c.80A>G) is located in coding exon 2 of the PTEN gene. The tyrosine at codon 27 is replaced by cysteine, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 2. This alteration was reported as de novo in a patient with macrocephaly, developmental delay, hypotonia, abnormal EEG, posterior periventricular multifocal white matter abnormalities and enlarged perivascular spaces with CSF isointense signal (Vanderver A et al. Am. J. Med. Genet. A, 2014 Mar;164A:627-33). 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 structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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