Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000543907 | SCV000655186 | pathogenic | Tumor predisposition syndrome 3 | 2023-12-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 117 of the POT1 protein (p.Arg117Cys). This variant is present in population databases (rs780936436, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of POT1 tumor predisposition syndrome (PMID: 26403419; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 475082). 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%. Experimental studies have shown that this missense change affects POT1 function (PMID: 26403419). For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV001755900 | SCV001987709 | uncertain significance | not provided | 2020-12-17 | criteria provided, single submitter | clinical testing | Identified in Spanish families with angiosarcoma and other cancers (Calvete 2015); Published functional studies demonstrate reduced recruitment of POT1 protein to telomeres and increased DNA damage markers, but no impact on telomerase activity in patient cells (Calvete 2015, Calvete 2019); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26403419, 28853721, 32033110, 28389767, 31510873) |
Ambry Genetics | RCV002456249 | SCV002612921 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-07-26 | criteria provided, single submitter | clinical testing | The p.R117C variant (also known as c.349C>T), located in coding exon 4 of the POT1 gene, results from a C to T substitution at nucleotide position 349. The arginine at codon 117 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration segregated in three Li-Fraumeni like families, including members affected with cardiac angiosarcomas, and other soft tissue sarcomas. Individuals in these families were shown to have reduced telomere bound POT1 levels, abnormally long telomeres, and increased telomere fragility (Calvete O et al. Nat Commun, 2015 Sep;6:8383). Mouse modeling using both embryonic fibroblasts and tissues with the R117C alteration showed longer telomeres than wild-type controls and complementation assays showed that R117C exerts dominant-negative effects at telomeres (Martínez P et al. PLoS Genet, 2022 06;18:e1010260). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Gene |
RCV000543907 | SCV001478027 | not provided | Tumor predisposition syndrome 3 | no assertion provided | literature only | Reported in 3 families with Li-Fraumeni-like and familial cardiac angiosarcoma |