ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.94ATT[1] (p.Ile33del) (rs1554893765)

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Total submissions: 5
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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 2019-03-05 reviewed by expert panel curation PTEN c.97_99delATT (p.I33del) 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 OR RNA, mini-gene, or other assay shows impact on splicing. (PMID 29706350) PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (Internal laboratory contributor SCV000616838.1) PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (Internal laboratory contributor SCV000616838.1)
GeneDx RCV000523445 SCV000616838 likely pathogenic not provided 2017-07-24 criteria provided, single submitter clinical testing The c.97_99delATT variant in the PTEN gene has previously been reported in at least one individual with Cowden disease (Nelen et al., 1999). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Thec.97_99delATT variant is an in-frame deletion that results in the loss of a single Isoleucine residue, denoted p.Ile33del within the phosphatase domain (Molinari et al., 2014). The residue removed by this deletion is conserved across species. Based on currently available evidence, c.97_99delATT is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded.
Ambry Genetics RCV000569550 SCV000671734 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-17 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 as a mutation in one of 13 Dutch Cowden syndrome patients, however justification for this classification was not provided (Nelen MR et al. Eur. J. Hum. Genet., 1999 Apr;7:267-73). The deleted amino acid position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000694225 SCV000822660 pathogenic PTEN hamartoma tumor syndrome 2018-10-03 criteria provided, single submitter clinical testing This variant, c.97_99delATT, results in the deletion of 1 amino acid of the PTEN protein (p.Ile33del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Cowden syndrome (PMID: 10234502), and individuals with features of Bannayan-Riley-Ruvalcaba syndrome or adult-onset Lhermitte-Duclos disease (Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 449088). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. 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

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