ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.320A>T (p.Asp107Val) (rs786204858)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000490579 SCV000930124 pathogenic PTEN hamartoma tumor syndrome 2019-06-25 reviewed by expert panel curation PTEN c.320A>T (p.Asp107Val) meets criteria to be classified as 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 (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 25418537) PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 28526761, PMID 23886400, internal laboratory contributor SCV000490750.2) PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (PMID 28526761, PMID 23886400, internal laboratory contributor SCV000490750.2) 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.
GeneDx RCV000413179 SCV000490750 pathogenic not provided 2018-02-23 criteria provided, single submitter clinical testing This variant is denoted PTEN c.320A>T at the cDNA level, p.Asp107Val (D107V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). This variant was observed in a family with Cowden syndrome (Paparo 2013). PTEN Asp107Val was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PTEN Asp107Val occurs at a position that is conserved across species and is located in the Within phosphatase domain (Molinari 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PTEN Asp107Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Herman Laboratory,Nationwide Children's Hospital RCV000490579 SCV000579267 pathogenic PTEN hamartoma tumor syndrome 2017-03-01 criteria provided, single submitter clinical testing
Invitae RCV000490579 SCV000829214 uncertain significance PTEN hamartoma tumor syndrome 2018-05-11 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 107 of the PTEN protein (p.Asp107Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with PTEN hamartoma tumor syndrome in two families (PMID: 28526761, 23886400). ClinVar contains an entry for this variant (Variation ID: 372481). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "C0"). The observation of one or more missense substitutions at this codon (p.Asp107Tyr) in affected individuals suggests that this may be a clinically significant residue (PMID: 23382303). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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