Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000567167 | SCV000674409 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-20 | criteria provided, single submitter | clinical testing | The p.G176R variant (also known as c.526G>A), located in coding exon 4 of the POT1 gene, results from a G to A substitution at nucleotide position 526. The glycine at codon 176 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV000652204 | SCV000774072 | uncertain significance | Tumor predisposition syndrome 3 | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 176 of the POT1 protein (p.Gly176Arg). This variant is present in population databases (rs774576173, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of POT1-related conditions (PMID: 34193977). ClinVar contains an entry for this variant (Variation ID: 486140). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POT1 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. |
Gene |
RCV001551221 | SCV001771683 | uncertain significance | not provided | 2023-05-05 | criteria provided, single submitter | clinical testing | Observed in an individual with papillary cystadenoma of the epididymis in conjunction with variants identified in other genes on a hereditary cancer multi-gene panel (Lopez et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25839328, 25710457, 28393830, 35496736, 36656928, 34193977) |
Genetic Services Laboratory, |
RCV001821690 | SCV002070165 | uncertain significance | not specified | 2020-02-27 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the POT1 gene demonstrated a sequence change, c.526G>A, in exon 8 that results in an amino acid change, p.Gly176Arg. This sequence change does not appear to have been previously described in patients with POT1-related disorders and has been described in the gnomAD database with an overall population frequency of 0.0014% (dbSNP rs774576173). The p.Gly176Arg change affects a moderately/ conserved amino acid residue located in a domain of the POT1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly176Arg substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly176Arg change remains unknown at this time. |
St. |
RCV000652204 | SCV004031241 | uncertain significance | Tumor predisposition syndrome 3 | 2023-07-25 | criteria provided, single submitter | clinical testing | The POT1 c.526G>A (p.Gly176Arg) missense change a maximum subpopulation frequency of 0.003% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POT1-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. |
Genome |
RCV000652204 | SCV001749928 | not provided | Tumor predisposition syndrome 3 | no assertion provided | phenotyping only | Variant interpreted as Uncertain significance and reported on 10-16-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. |