ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.44G>A (p.Arg15Lys) (rs398123324)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000462758 SCV000840474 likely pathogenic PTEN hamartoma tumor syndrome 2020-03-23 reviewed by expert panel curation PTEN c.44G>A (p.Arg15Lys) 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). 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 SCV000573362.4) 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. PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3. (PMID 25875300) PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000573362.4)
Invitae RCV000462758 SCV000541593 uncertain significance PTEN hamartoma tumor syndrome 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 15 of the PTEN protein (p.Arg15Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 404147). This variant has been reported to affect PTEN protein function (PMID: 25875300). 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.
GeneDx RCV000480861 SCV000573362 likely pathogenic not provided 2017-03-13 criteria provided, single submitter clinical testing The R15K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, functional studies show that while R15K does not inhibit nuclear accumulation of PTEN, it does show severely diminished or completely abrogated phosphatase activity in vitro (Gil et al., 2015). The R15K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R15K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and is located within the phosphatase domain and the N-terminal nuclear localization signal (Molinari et al., 2013; Gil et al., 2015). A missense variant in the same residue (R15S) has been reported in the Human Gene Mutation Database in association with Cowden syndrome (Nagy et al., 2011; Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, R15K is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded.

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