ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.737C>T (p.Pro246Leu) (rs587782350)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131292 SCV000186263 pathogenic Hereditary cancer-predisposing syndrome 2016-11-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s)
Center for Human Genetics, Inc RCV000660237 SCV000782243 pathogenic Cowden syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
ClinGen PTEN Variant Curation Expert Panel RCV000613031 SCV000840469 pathogenic PTEN hamartoma tumor syndrome 2017-10-18 reviewed by expert panel curation PTEN c.737C>T (p.P246L) 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_VS: At least two proven OR one proven plus two assumed de novo observations in a patient with the disease and no family history. (PMID 23934111, internal laboratory contributor(s) SCV000222227.10) PS4: Probands with phenotype specificity score of 4-15.5. (PMID 24375884, PMID 10076877, PMID 22261759, PMID 23934111, internal laboratory contributor(s) SCV000222227.10) 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.
Counsyl RCV000660237 SCV000786146 likely pathogenic Cowden syndrome 1 2018-03-07 criteria provided, single submitter clinical testing
GeneDx RCV000212883 SCV000222227 pathogenic not provided 2018-12-13 criteria provided, single submitter clinical testing This variant is denoted PTEN c.737C>T at the cDNA level, p.Pro246Leu (P246L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant has been observed in individuals with Bannayan-Riley-Ruvalcaba syndrome and has been reported as de novo in a child presenting with vascular anomalies and macrocephaly (Otto 1999, Hobert 2012, Allen 2013). Yeast-based assays studying the functional impact of PTEN Pro246Leu by Rodriguez-Escudero et. al. (2011) found growth rescue comparable to wild-type but a significant impact on phosphatase activity. Likewise, Zhou et al. (2003) reported weak PTEN expression and elevated P-Akt levels in a dysplastic gangliocytoma from an individual harboring this variant in their germline. PTEN Pro246Leu 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. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. PTEN Pro246Leu occurs at a position that is conserved across species and is located in the C2 domain (Wang 2008). Based on current information, we consider this variant to be pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000660237 SCV000840053 pathogenic Cowden syndrome 1 2017-06-03 criteria provided, single submitter clinical testing This c.737C>T (p.Pro246Leu) variant was detected in 3 members of a family with Bannayan-Riley-Ruvalcaba syndrome (BRRS) [PMID 10400993]. BRRS is allelic to Cowden syndrome and is characterized by macrocephaly, hamartomatous intestinal polyposis, lipomas, and pigmented macules of the glans penis. The variant was further detected de novo in a cohort of 264 trio diagnosed with seizure. The patient had infantile spasms in addition to vascular anomalies and macrocephaly [PMID 23934111]. We have observed this variant, de novo, in a patient with autism in our internal database. This c.737C>T (p.Pro246Leu) variant was not observed in the gnomAD population database. Proline at amino acid position 246 is conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Pro246Leu to be deleterious. This variant is thus classified as pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000613031 SCV000711446 likely pathogenic PTEN hamartoma tumor syndrome 2017-05-24 criteria provided, single submitter clinical testing The p.Pro246Leu variant in PTEN has been reported in at least 3 individuals with PTEN-associated phenotypes: 1 with Bannayan-Riley-Ruvalcaba syndrome (BRRS), 1 with Lhermitte-Duclos disease (LDD), and 1 with colon cancer and segregated with BRRS in 2 affected relatives (Marsh 1999, Otto 1999, Zhou 2003, Hobert 2012, Su sswein 2016). In addition, it was reported as a de novo occurrence in an infant with infantile spasms and clinical features of a PTEN hamartoma tumor syndrome ( Allen 2013). Functional studies provide some evidence that the p.Pro246Leu varia nt is associated with decreased protein activity (Rodriguez-Escudero 2011). This variant was absent from large population studies. In summary, although addition al studies are required to fully establish its clinical significance, the p.Pro2 46Leu variant is likely pathogenic.

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