Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000165307 | SCV000216029 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2014-07-23 | criteria provided, single submitter | clinical testing | The p.C124G variant (also known as c.370T>G), located in coding exon 5 of the PTEN gene, results from a T to G substitution at nucleotide position 370. The cysteine at codon 124 is replaced by glycine, an amino acid with highly dissimilar properties. This alteration occurs in a catalytically active residue responsible for dephosphorylating the phospholipid second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), which is critical for tumor suppressor function (Xiao Y, Cell. Signal. 2007 Jul; 19(7):1434-45. Chia JY, Biochim. Biophys. Acta 2010 Sep; 1804(9):1785-95). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 51000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV002517621 | SCV003439624 | pathogenic | PTEN hamartoma tumor syndrome | 2025-01-23 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 124 of the PTEN protein (p.Cys124Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Cowden syndrome (Inviate). ClinVar contains an entry for this variant (Variation ID: 185817). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTEN protein function. Experimental studies have shown that this missense change affects PTEN function (PMID: 9823298, 10657643, 19000654, 20100827). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Cys124 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15211648; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |