Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000533554 | SCV000655185 | uncertain significance | Tumor predisposition syndrome 3 | 2023-01-22 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with cardiac angiosarcoma and/or melanoma (PMID: 28853721, 33050356). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 116 of the POT1 protein (p.Pro116Leu). ClinVar contains an entry for this variant (Variation ID: 475081). 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. Experimental studies have shown that this missense change affects POT1 function (PMID: 33050356). 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. |
| Ambry Genetics | RCV002456248 | SCV002617591 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-11-16 | criteria provided, single submitter | clinical testing | The p.P116L variant (also known as c.347C>T), located in coding exon 4 of the POT1 gene, results from a C to T substitution at nucleotide position 347. The proline at codon 116 is replaced by leucine, an amino acid with similar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with POT1-related disease (Ambry internal data). This alteration has been reported in a patient with sporadic cardiac angiosarcoma (Calvete O et al. Eur. J. Hum. Genet., 2017 11;25:1278-1281). It was also reported in an individual with multiple primary melanomas and breast cancer diagnosis; however, this individual also had a CHEK2 variant (Stolarova L et al. Biomedicines, 2020 Oct;8:). Functional studies showed that p.P116L could bind TPP1, but was unable to bind telomeric DNA (Stolarova L et al. Biomedicines, 2020 Oct;8). Based on internal structural analysis, P116L is more disruptive to the structure of the OB1 domain than a nearby pathogenic variant (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Institute of Human Genetics, |
RCV003985380 | SCV004801715 | likely pathogenic | See cases | 2024-02-23 | criteria provided, single submitter | clinical testing | ACMG categories: PS3,PM2,PP3 |