ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.407G>A (p.Cys136Tyr) (rs786204859)

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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 RCV000552515 SCV000840468 pathogenic PTEN hamartoma tumor syndrome 2017-10-18 reviewed by expert panel curation PTEN c.407G>A (p.C136Y) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). 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) SCV000222113.9) PS3: Phosphatase activity <50% of wild-type OR RNA, mini-gene, or other assay shows impact on splicing. (PMID 10866302) PM2: Absent in large sequenced populations (PMID 27535533). 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. PS4_P: Probands with specificity score of 1-1.5. (PMID 9735393, internal laboratory contributor(s) SCV000222113.9)
GeneDx RCV000169797 SCV000222113 pathogenic not provided 2017-02-21 criteria provided, single submitter clinical testing The C136Y variant in the PTEN gene was observed in at least one individual with features suspicious of, but not diagnostic for, PTEN-hamartoma tumor syndrome (Scala et al., 1998). This variant has also been reported in other individuals, however no clinical information was provided (Heald et al., 2010, Ngeow et al., 2011, Pilarski et al., 2011). Functional studies show that the C136Y variant nullifies phosphatase activity of PTEN (Han et al., 2000). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C136Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This variant occurs at a position that is conserved across species and is located in the phosphatase domain and ATP binding motif (Lobo et al., 2009; Molinari et al., 2014). In addition, a different missense variant at the same residue, C136R, has been reported previously in association with PHTS, supporting the functional importance of this region of the protein (Kubo et al., 2000; He et al., 2013; Paparo et al., 2013; Bubien et al., 2013). Based on currently available evidence, we consider C136Y to be pathogenic.
Ambry Genetics RCV000217011 SCV000274675 pathogenic Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing Other strong data supporting pathogenic classification;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Well-characterized mutation at same position;Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000552515 SCV000645580 pathogenic PTEN hamartoma tumor syndrome 2019-04-08 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 136 of the PTEN protein (p.Cys136Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families with Cowden syndrome (CD) and Bannayan-Riley-Ruvalcaba syndrome (PMID: 9735393, 20600018, 21659347, 21194675). ClinVar contains an entry for this variant (Variation ID: 189406). A different missense substitution at this codon (p.Cys136Arg) has been determined to be pathogenic (PMID: 10848731, 20600018, 24778394, 23886400, 21659347). This suggests that the cysteine residue is critical for PTEN protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this variant was expressed together with the wild-type allele in pathological tissue from an individual with Cowden disease, and that it resulted in disruption of the phosphatase activity of the PTEN protein (PMID: 10866302, 9735393). For these reasons, this variant has been classified as Pathogenic.

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