Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clingen PTEN Variant Curation Expert Panel, |
RCV002527058 | SCV004183301 | likely pathogenic | PTEN hamartoma tumor syndrome | 2023-08-04 | reviewed by expert panel | curation | NM_000314.8(PTEN):c.44G>C (p.Arg15Thr) 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. [internal laboratory contributor(s)] 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 -1.2. PM2_Supporting: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (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: in silico REVEL score of 0.87 (>0.7) |
| Ambry Genetics | RCV000491951 | SCV000580035 | uncertain significance | Hereditary cancer-predisposing syndrome | 2014-04-17 | criteria provided, single submitter | clinical testing | The p.R15T variant (also known as c.44G>C), located in coding exon 1 of the PTEN gene, results from a G to C substitution at nucleotide position 44. The arginine at codon 15 is replaced by threonine, an amino acid with similar properties. 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. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 35,000 alleles tested) in our clinical cohort (includes this individual). While this alteration has not been reported in the literature to date, a different alteration at the same codon, p.R15S, was identified in an individual who met NCCN clinical criteria for Cowden syndrome with follicular thyroid cancer, macrocephaly, and GI hamartomas (Nagy, R et al. Thyroid. 2011 May;21(5):505-10). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign yet deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.R15T remains unclear. |
| Labcorp Genetics |
RCV002527058 | SCV003319044 | pathogenic | PTEN hamartoma tumor syndrome | 2022-07-05 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 15 of the PTEN protein (p.Arg15Thr). This missense change has been observed in individual(s) with clinical features of Cowden syndrome (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 428243). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). This variant disrupts the p.Arg15 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16773562, 17942903, 21417916, 21659347, 24375884, 25875300, 29706350). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |