ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.367C>T (p.His123Tyr) (rs786204931)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000169876 SCV000222205 pathogenic not provided 2017-06-28 criteria provided, single submitter clinical testing This pathogenic variant is denoted PTEN c.367C>T at the cDNA level, p.His123Tyr (H123Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). While this variant has not, to our knowledge, been published in the literature as a germline pathogenic variant it has been published as a somatic mutation in endometrial cancer which prompted its evaluation on a functional level (Tashiro 1997). Two in vitro function assays both concluded that PTEN His123Tyr results in the complete loss of phosphatase activity (Rodriguez-Escudero 2011, Myers 1997). Additionally, two other another missense pathogenic variants at the same residue, His123Asp and His123Arg, have been published in association with Cowden syndrome (Bussaglia 2002, Nelen 1997). PTEN His123Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PTEN His123Tyr occurs at a position that is highly conserved across species and is located within the phosphatase tensin-type domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000554647 SCV000645574 likely pathogenic PTEN hamartoma tumor syndrome 2018-07-19 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 123 of the PTEN protein (p.His123Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in the germline of individuals with a PTEN-related disease. ClinVar contains an entry for this variant (Variation ID: 189486). This variant falls in the conserved P-loop in the active site of the PTEN protein (PMID: 10555148). Multiple experimental studies have shown that this variant abolishes PTEN kinase activity, and leads to cell proliferation, anchorage-independent growth, and loss of cell cycle progression inhibition (PMID: 21828076, 10555148, 16619501, 10772829, 9256433). The histidine 123 residue is known to be critical for PTEN protein function. Other missense substitutions at this position (His123Asp, His123Arg, His123Gln) also disrupt PTEN function and have been reported in individuals affected with Cowden syndrome (PMID: 11918710, 9259288, 21291452). In summary, this variant is a rare missense change that disrupts PTEN function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000169876 SCV000888592 likely pathogenic not provided 2018-03-01 criteria provided, single submitter clinical testing

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