Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000218300 | SCV000274246 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-21 | criteria provided, single submitter | clinical testing | The p.I303S variant (also known as c.908T>G), located in coding exon 8 of the PTEN gene, results from a T to G substitution at nucleotide position 908. The isoleucine at codon 303 is replaced by serine, an amino acid with dissimilar properties. This variant demonstrated wild-type-like intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally wild-type-like (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV000475006 | SCV000541586 | uncertain significance | PTEN hamartoma tumor syndrome | 2025-01-23 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 303 of the PTEN protein (p.Ile303Ser). This variant is present in population databases (rs772018727, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 230633). 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) indicates that this missense variant is not expected to disrupt PTEN protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Color Diagnostics, |
RCV000218300 | SCV001360394 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-03-04 | criteria provided, single submitter | clinical testing | |
| Lupski Lab, |
RCV000218300 | SCV005402552 | likely benign | Hereditary cancer-predisposing syndrome | 2024-04-12 | criteria provided, single submitter | curation | Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).For PTEN, two assays measuring activity and abundance were used. If the abundance was categorized as "wt-like" or "possibly wt-like," BS3_Supporting evidence was used. Furthermore, if the cumulative score was greater than -5, BS3_moderate evidence was used. This variant GRCh38:10:87961000:T>G was assigned evidence codes ['BS3_Supporting', 'BP4'] and an overall classification of Likely benign |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV004998450 | SCV005624710 | uncertain significance | not provided | 2024-06-13 | criteria provided, single submitter | clinical testing | The PTEN c.908T>G (p.Ile303Ser) variant has not been reported in individuals with PTEN-related conditions in the published literature. Experimental studies indicate this variant has neutral effect on PTEN lipid phosphatase activity and protein abundance (PMIDs: 29706350 (2018), 29785012 (2018)). The frequency of this variant in the general population, 0.000008 (2/251268 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. |