ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.830C>G (p.Thr277Arg) (rs398123329)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel 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 <span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">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 withCowden 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 PTENIHC expression (BanneauG, 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 thisvariant is significantly greaterthan a known pathogenic variant in the same amino acidposition(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.
Invitae RCV000536465 SCV000645627 pathogenic PTEN hamartoma tumor syndrome 2019-01-03 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). 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). This variant has been reported to affect PTEN protein function (PMID: 29706350). For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.