Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV000771423 | SCV000903787 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-05 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with isoleucine at codon 275 of the PTEN protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PTEN-related disorders in the literature. This variant has been identified in 1/28024 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Labcorp Genetics |
RCV000821963 | SCV000962739 | uncertain significance | PTEN hamartoma tumor syndrome | 2024-12-22 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 275 of the PTEN protein (p.Val275Ile). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 627703). 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. |
| Ambry Genetics | RCV000771423 | SCV002676092 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-02-12 | criteria provided, single submitter | clinical testing | The p.V275I variant (also known as c.823G>A), located in coding exon 8 of the PTEN gene, results from a G to A substitution at nucleotide position 823. The valine at codon 275 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. |
| Baylor Genetics | RCV004569430 | SCV005052553 | uncertain significance | Glioma susceptibility 2 | 2024-03-11 | criteria provided, single submitter | clinical testing | |
| Lupski Lab, |
RCV000771423 | SCV005402543 | 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 GRCh38:10:87960915:G>A was assigned evidence codes ['BP4', 'BS1_Supporting'] and an overall classification of Likely benign |