Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000574800 | SCV000665300 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-01 | criteria provided, single submitter | clinical testing | The p.Y180H variant (also known as c.538T>C), located in coding exon 6 of the PTEN gene, results from a T to C substitution at nucleotide position 538. The tyrosine at codon 180 is replaced by histidine, an amino acid with similar properties. In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was determined to be wild-type-like (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). This amino acid position is well 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. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000760050 | SCV000889804 | uncertain significance | not provided | 2018-03-22 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000808114 | SCV000948206 | uncertain significance | PTEN hamartoma tumor syndrome | 2024-09-14 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 180 of the PTEN protein (p.Tyr180His). This variant is present in population databases (rs746280047, gnomAD 0.003%). 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: 481129). 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. |
| ARUP Laboratories, |
RCV000760050 | SCV001477860 | uncertain significance | not provided | 2019-11-06 | criteria provided, single submitter | clinical testing | The PTEN c.538T>C; p.Tyr180His variant (rs746280047), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 481129). This variant is found on a single chromosome in the Genome Aggregation Database (1/251234 alleles), indicating it is not a common polymorphism. The tyrosine at codon 180 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Tyr180His variant is uncertain at this time. |
| Lupski Lab, |
RCV000574800 | SCV005402533 | 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 GRCh38:10:87952163:T>C was assigned evidence codes ['BS3_Supporting', 'BP4'] and an overall classification of Likely benign |