Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clingen PTEN Variant Curation Expert Panel, |
RCV000694225 | SCV000930148 | likely pathogenic | PTEN hamartoma tumor syndrome | 2023-08-04 | reviewed by expert panel | curation | PTEN c.97_99delATT (c.94ATT[1]) (p.Ile33del) 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). PS3_Moderate: Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350. PM2_Supporting: Absent in large sequenced populations (PMID 27535533). PM6_Strong: An individual with a highly specific phenotype (Internal laboratory contributor SCV000616838.1). PP1: Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. (PMID 10234502 , internal laboratory contributor SCV002559099.1) |
Gene |
RCV000523445 | SCV000616838 | pathogenic | not provided | 2022-02-07 | criteria provided, single submitter | clinical testing | In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate a damaging effect: significantly reduced lipid phosphatase activity in a high-throughput assay (Mighell 2018); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21194675, 18558293, 10923032, 23674493, 9765621, 30325992, 33163849, 31594918, 10234502, 29706350, 24475377) |
Ambry Genetics | RCV000569550 | SCV000671734 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-11-17 | criteria provided, single submitter | clinical testing | The c.97_99delATT variant (also known as p.I33del) is located in coding exon 2 of the PTEN gene. This variant results from an in-frame ATT deletion at nucleotide positions 97 to 99. This results in the in-frame deletion of an isoleucine at codon 33. This alteration has been reported in multiple individuals with PTEN hamartoma tumor syndrome (Ambry internal data; Nelen MR et al. Eur. J. Hum. Genet., 1999 Apr;7:267-73; Busch RM et al. Transl Psychiatry, 2019 10;9:253). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Lee CU et al. Angew Chem Int Ed Engl, 2015 Nov;54:13796-800). The deleted amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Invitae | RCV000694225 | SCV000822660 | pathogenic | PTEN hamartoma tumor syndrome | 2023-10-13 | criteria provided, single submitter | clinical testing | This variant, c.97_99del, results in the deletion of 1 amino acid(s) of the PTEN protein (p.Ile33del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with features of Bannayan-Riley-Ruvalcaba syndrome or adult-onset Lhermitte-Duclos disease and Cowden syndrome (PMID: 10234502; Invitae; external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 449088). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. |
Mendelics | RCV000694225 | SCV001138124 | likely pathogenic | PTEN hamartoma tumor syndrome | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Center for Genomic Medicine, |
RCV000523445 | SCV002549951 | likely pathogenic | not provided | 2023-08-15 | criteria provided, single submitter | clinical testing | |
Centre de Biologie Pathologie Génétique, |
RCV002274052 | SCV002559099 | pathogenic | Neurodevelopmental delay | criteria provided, single submitter | clinical testing |