ClinVar Genomic variation as it relates to human health

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)

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.

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 amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

The variant is rare in gnomADv4 (2/1461660 alleles, frequency : 0.00014%). Arginine at position 117 is an amino acid that appears to be highly conserved in evolution. The variant is located in the Telomeric single stranded DNA binding domain. The variant has been describred in 3 “Li-Fraumeni-like” families with multiple cancers including cardiosarcomas but also melanomas or lung cancers. In silico, in vitro and in vivo studies in cells showed that the variant reduces POT1 binding to telomeres and increases telomere length and fragility (PMID:26403419_2015). Another study by the same author showed the presence of a POT1 mutation in 20% of families with angiosarcomas and 10% of individuals with sporadic angio or cardiosarcoma (PMID:28853721_2017). The patient's phenotype and family history are compatible with the pathology associated with POT1 gene.

Reported in 3 families with Li-Fraumeni-like and familial cardiac angiosarcoma