ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.370T>C (p.Cys124Arg) (rs121909223)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000700581 SCV000930112 pathogenic PTEN hamartoma tumor syndrome 2019-06-25 reviewed by expert panel curation PTEN c.370T>C (p.Cys124Arg) meets criteria to be classified as 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). PS3: Phosphatase activity <50% of wild type (PMID 10866302, PMID 29706350) PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (internal laboratory contributor SCV000568254.4) 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). 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 SCV000568254.4)
GeneDx RCV000485809 SCV000568254 pathogenic not provided 2018-03-07 criteria provided, single submitter clinical testing This pathogenic variant is denoted PTEN c.370T>C at the cDNA level, p.Cys124Arg (C124R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). This variant has been reported in association with Cowden syndrome in at least three individuals reported to have macrocephaly and/or multiple features characteristic of PTEN-related disorder (Nelen 1997, Marsh 1998). In vitro functional assays concluded that PTEN Cys124Arg results in the complete loss of phosphatase activity (Han 2000). In addition, a PTEN knockin mouse model with the heterozygous PTEN Cys124Arg variant was observed to have organ-selective cancer predisposition and proliferative lesions consistent with Cowden syndrome and nearly absent detectable Pten protein; Cys124Arg homozygous mouse models exhibited abnormal embryonic development and lethality (Wang 2010). Of note, PTEN Cys124Arg is found in exon 5 of the PTEN gene, which has been described as a mutational hot-spot, and, in one study, almost half of all Cowden syndrome-associated PTEN mutations were identified in this exon (Marsh 1998). PTEN Cys124Arg was not observed in large population cohorts (Lek 2016). This variant is located within the Phosphatase Core Domain and the ATP binding motif (Lee 1999, Lobo 2009, Molinari 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000700581 SCV000829340 pathogenic PTEN hamartoma tumor syndrome 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 124 of the PTEN protein (p.Cys124Arg). The arginine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Cowden syndrome or Cowden syndrome-like (PMID: 9259288, 9467011, 9832031, 21194675). ClinVar contains an entry for this variant (Variation ID: 7817). Experimental studies have shown that this missense change abolishes the phospatase activity of the PTEN protein (PMID: 10866302). Moreover, a p.Cys124Arg PTEN knockin heterozygous mouse model has exhibited a high incidence of tumor lesions consistent with Cowden syndrome and low levels of PTEN protein in the normal tissue due a lack of stability (PMID: 20194734). The p.Cys124Arg knockin homozygous mouse model presented abnormal development and early embryonic lethality (PMID: 20194734). The p.Cys124 amino acid residue in PTEN is a catalytically critical residue located in the active site phosphate binding loop of the PTEN protein (PMID: 10555148, 17324556) and has been determined to be clinically significant (PMID: 25647146, 22962422, 21828076). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001020947 SCV001182495 pathogenic Hereditary cancer-predisposing syndrome 2019-10-15 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification;Other strong data supporting pathogenic classification;Rarity in general population databases (dbsnp, esp, 1000 genomes);Well-characterized mutation at same position
OMIM RCV000008261 SCV000028468 pathogenic Cowden syndrome 1 1997-08-01 no assertion criteria provided literature only

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