Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000735264 | SCV000863477 | likely pathogenic | PTEN hamartoma tumor syndrome | 2018-04-06 | reviewed by expert panel | curation | PTEN c.368A>G (p.H123R) PTEN c.368A>G (p.H123R) 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). PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. 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. (PMID 10234502) 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. |
| Gene |
RCV000518927 | SCV000617322 | pathogenic | not provided | 2017-06-28 | criteria provided, single submitter | clinical testing | This variant is denoted PTEN c.368A>G at the cDNA level, p.His123Arg (H123R) at the protein level,and results in the change of a Histidine to an Arginine (CAC>CGC). This variant was found to occur de novo in apatient with Cowden syndrome (Nelen 1997, Nelen 1999). Additionally, other amino acid changes at the His123residue - PTEN His123Gln, His123Tyr, and His123Asp - have been reported in individuals with clinical historiesconsistent with PTEN Hamartoma Tumor syndrome and on functional interrogation demonstrated absent or decreasedphosphatase activity and inability to rescue or regulate cell growth (Myers 1997, Lee 1999, Bussaglia 2002, Rodriguez-Escudero 2011, Kersseboom 2011, Spinelli 2015, Hansen-Kiss 2017). PTEN His123Arg was not observed in largepopulation cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). SinceHistidine and Arginine share similar properties, this is considered a conservative amino acid substitution. PTENHis123Arg occurs at a position that is conserved across species and is located in an ATP binding motif andphosphatase core domain (Lee 1999, Lobo 2009, Molinari 2014). In silico analyses predict that this variant is probablydamaging to protein structure and function. Based on currently available evidence, we consider this variant to bepathogenic |
| OMIM | RCV000008260 | SCV000028467 | pathogenic | Cowden syndrome 1 | 1997-08-01 | no assertion criteria provided | literature only |