Submissions for variant NM_000314.8(PTEN):c.80A>G (p.Tyr27Cys)

dbSNP: rs886041877

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000471888	SCV001244234	likely pathogenic	PTEN hamartoma tumor syndrome	2023-10-11	reviewed by expert panel	curation	NM_000314.8(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 (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM6_S: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history in a proband(s) with phenotype specificity score of 1-1.5 (PMID: 24375884). PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.648 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PM2_P: 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. PP3: REVEL score > 0.7 (score of this variant = 0.991)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471888	SCV000541611	likely pathogenic	PTEN hamartoma tumor syndrome	2021-02-13	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with PTEN hamartoma tumor syndrome (PMID: 24375884). In at least one individual the variant was observed to be de novo. Experimental studies have shown that this variant affects PTEN protein function (PMID:32350270). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is not present in population databases (ExAC no frequency). 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.
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.
Myriad Genetics, Inc.	RCV003449110	SCV004188754	likely pathogenic	Cowden syndrome 1	2023-09-26	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 29785012, 32350270].