ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.103A>G (p.Met35Val) (rs876659443)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000548863 SCV000840461 likely pathogenic PTEN hamartoma tumor syndrome 2020-03-23 reviewed by expert panel curation PTEN c.103A>G (p.Met35Val) 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000275912.5) PM2: Absent in large sequenced populations (PMID 27535533). PS4_M: Probands with phenotype specificity score of 2-3.5. (Internal laboratory contributor(s) SCV000565444.4, SCV000275912.5) 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.
Ambry Genetics RCV000218360 SCV000275912 likely pathogenic Inborn genetic diseases 2016-09-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
GeneDx RCV000479090 SCV000565444 likely pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing This variant is denoted PTEN c.103A>G at the cDNA level, p.Met35Val (M35V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant was observed in at least two individuals with features of PTEN hamartoma tumor syndrome (Heald 2010, Tan 2011, Hagelstrom 2016). PTEN Met35Val was not observed in large population cohorts (Lek 2016). This variant is located in the phosphatase domain (Molinari 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider PTEN Met35Val to be a likely pathogenic variant.
Invitae RCV000548863 SCV000645545 likely pathogenic PTEN hamartoma tumor syndrome 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 35 of the PTEN protein (p.Met35Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of PTEN hamartoma tumor syndrome (PMID: 26468640, 21194675, 27531073, 30311380, external communication). ClinVar contains an entry for this variant (Variation ID: 231916). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Met35 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9425889, 21828076, 25875300, 17942903). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color RCV000771914 SCV000904681 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000771914 SCV001178150 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-31 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other strong data supporting pathogenic classification;Rarity in general population databases (dbsnp, esp, 1000 genomes);Structural Evidence
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198718 SCV001369713 likely pathogenic Iris coloboma; Broad hallux; Broad thumb; Macrocephalus; Dolichocephaly; Arnold-Chiari malformation; Sacral lipoma 2018-12-05 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. This variant was detected in heterozygous state.

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