Submissions for variant NM_000314.8(PTEN):c.212G>A (p.Cys71Tyr)

dbSNP: rs1554897856

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV001205381	SCV005044862	pathogenic	PTEN hamartoma tumor syndrome	2024-02-09	reviewed by expert panel	curation	NM_000314.8(PTEN):c.212G>A (p.Cys71Tyr) meets criteria to be classified as 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). PS2_VS: One proven plus two assumed de novo observations in a patient with the disease and no family history. (internal laboratory contributors: SCV003918479.1, SCV001376634.5) PS3_M: Functional studies showing a damaging effect on protein function. Phosphatase activity <= -1.11 per Mighell et al. 2018 (PMID: 29706350). This variant: score of -1.57581. 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 =0.957) PM2_P: Absent in the gnomAD cohort. (PMID 27535533).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001205381	SCV001376634	pathogenic	PTEN hamartoma tumor syndrome	2023-07-29	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 936561). This missense change has been observed in individual(s) with PTEN-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 71 of the PTEN protein (p.Cys71Tyr). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812250	SCV001473068	uncertain significance	not provided	2020-06-17	criteria provided, single submitter	clinical testing	The PTEN c.212G>A; p.Cys71Tyr variant is reported in the literature in an individual referred for unspecified clinical PTEN testing (Pilarski 2011) and also in a glioma tumor sample (Kato 2000). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 71 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Further, functional characterization of the purified p.Cys71Tyr protein showed loss of enzymatic activity (Kato 2000), though this finding has not been confirmed by other assays. While existing evidence suggests a possible role of p.Cys71Tyr variant in disease, due to limited information, its clinical significance is uncertain at this time. References: Kato H et al. Functional evaluation of p53 and PTEN gene mutations in gliomas. Clin Cancer Res. 2000;6(10):3937-3943. Pilarski R et al. Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. J Med Genet. 2011;48(8):505-512.
GeneDx	RCV001812250	SCV003918479	pathogenic	not provided	2023-04-10	criteria provided, single submitter	clinical testing	Reported as a variant of uncertain significance in a patient undergoing PTEN genetic testing; clinical information not provided (Pilarski et al, 2011); Published functional studies demonstrate a damaging effect, as variant inactivates phosphoinositide phosphatase activity (Han et al, 2000); Not observed at significant frequency 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: 14642363, 21659347, 22413991, 34504233, 33152507, 10866302, 24475377, 19457929)
Myriad Genetics, Inc.	RCV003449650	SCV004188732	likely pathogenic	Cowden syndrome 1	2023-09-27	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: 10866302, 11051241].
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796372	SCV005415665	likely pathogenic	Macrocephaly-autism syndrome; Familial meningioma; Glioma susceptibility 2; Familial prostate cancer; Cowden syndrome 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3+PP2