Submissions for variant NM_000314.8(PTEN):c.830C>G (p.Thr277Arg)

dbSNP: rs398123329

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000536465	SCV001335276	likely pathogenic	PTEN hamartoma tumor syndrome	2020-03-23	reviewed by expert panel	curation	PTEN c.830C>G (p.Thr277Arg) 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). PS3: Phosphatase activity <50% of wild type (PMID 29706350) PM2: Absent in large sequenced populations PP1_M: Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. (PMID 23335809) 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.
Ambry Genetics	RCV000491643	SCV000580063	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-04-15	criteria provided, single submitter	clinical testing	The p.T277R variant (also known as c.830C>G), located in coding exon 8 of the PTEN gene, results from a C to G substitution at nucleotide position 830. The threonine at codon 277 is replaced by arginine, an amino acid with similar properties. This alteration was detected in the germline of an individual diagnosed with Cowden syndrome (CS) and breast cancer. This individual's tumor was noted to have an expression profile similar to that of other CS breast tumors, and absent PTEN IHC expression (Banneau G, Breast Cancer Res. 2010;12(4):R63). This residue occurs in a match for a FHA domain consensus recognition sequence, suggesting that it is a potential binding site (Okumura K et al. Proc. Natl. Acad. Sci. U.S.A. 2005 Feb;102(8):2703-6). In addition, the destabilizing energy of this variant is significantly greater than a known pathogenic variant in the same amino acid position (Ambry internal data). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6480 samples (12960 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 200000 alleles tested) in our clinical cohort. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000536465	SCV000645627	pathogenic	PTEN hamartoma tumor syndrome	2019-01-03	criteria provided, single submitter	clinical testing	This variant has been observed in several individuals affected with PTEN-related conditions (PMID: 20712882, 23335809). ClinVar contains an entry for this variant (Variation ID: 428268). For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect PTEN protein function (PMID: 29706350). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with arginine at codon 277 of the PTEN protein (p.Thr277Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine.
Myriad Genetics, Inc.	RCV003449278	SCV004189510	likely pathogenic	Cowden syndrome 1	2023-10-02	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic.  Functional studies indicate this variant impacts protein function [PMID: 29785012]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23335809].