ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.610C>G (p.Pro204Ala) (rs786204868)

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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 RCV001078173 SCV001244252 likely pathogenic PTEN hamartoma tumor syndrome 2019-11-22 reviewed by expert panel curation PTEN c.610C>G (p.Pro204Ala) 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 SCV000222125.5) 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000222125.5)
GeneDx RCV000505702 SCV000222125 likely pathogenic not provided 2017-03-27 criteria provided, single submitter clinical testing The P204A variant has previously been reported in an individual with malignant mucosal melanoma, but has not been reported in the germline (Liang et al., 2015; abstract only). A different missense substitution at the same amino acid residue (P204S) has been reported in association with glioblastoma, and functional studies showed disruption of both membrane binding and protein structure, resulting in impaired PTEN tumor suppressor function due to the P204S variant (Georgescu et al., 2000). The P204A variant 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. This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (F200S, T202I, M205V, S207R) have been reported in association with PTEN-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available evidence, P204S is likely pathogenic. However, the possibility that it is benign cannot be excluded.
Ambry Genetics RCV000219704 SCV000275034 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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