ClinVar Genomic variation as it relates to human health

The frequency of this variant in the general population, 0.0003 (3/9890 chromosomes in Ashkenazi Jewish subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in an individual with melanoma (PMID: 30586141 (2018), 30451293 (2018), 24686846 (2014)) and chronic lymphocytic leukemia (PMID: 34193977 (2021)). This variant has also been shown to have a deleterious effect on POT1 protein function (PMID: 30586141 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 78 of the POT1 protein (p.Ile78Thr). This variant is present in population databases (no rsID available, gnomAD 0.03%). This missense change has been observed in individuals with clinical features consistent with POT1-related conditions (PMID: 24686846, 30586141, 34193977; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 475073). 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: 30586141). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The p.I78T variant (also known as c.233T>C), located in coding exon 3 of the POT1 gene, results from a T to C substitution at nucleotide position 233. The isoleucine at codon 78 is replaced by threonine, an amino acid with similar properties. This variant has been reported in at least three unrelated individuals with melanoma without other clear mutations identified (Wong K et al. JAMA Dermatol, 2019 05;155:604-609; Potrony M et al. Br J Dermatol, 2019 07;181:105-113; Goldstein AM et al. JAAD Int, 2023 Jun;11:43-51; Shi J et al. Nat. Genet. 2014 May;46:482-6; DeBoy EA et al. N Engl J Med, 2023 May). This alteration was also identified in an individual diagnosed with CML and a second individual diagnosed with CLL (Lim TL et al. Leukemia, 2022 01;36:283-287). Haplotype analysis performed in unrelated carriers of p.I78T identified a common haplotype, suggestive of a founder event (Wong K et al. JAMA Dermatol, 2019 05;155:604-609). 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). However, this variant has also been identified in individuals without melanoma or other POT1 related tumors (Ambry internal data). Multiple in vitro functional studies indicated that the p.I78T variant was unable to bind telomeres compared to wild type, resulting in elongated telomeres following ectopic expression (Wong K et al. JAMA Dermatol, 2019 05;155:604-609; DeBoy EA et al. N Engl J Med, 2023 May). Direct measurements from patient cells also showed longer telomeres as compared to controls (DeBoy EA et al. N Engl J Med, 2023 May). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Observed in individuals with multiple primary melanomas and/or with familial melanoma; however, several unaffected carriers were also identified (PMID: 24686846, 30451293, 37140166, 36876055); Observed in individuals with lymphoid or myeloid malignancies, as well as individuals with thyroid cancer (PMID: 34193977, 37140166); Published functional studies demonstrate a damaging effect: disrupted telomere binding and telomere elongation (PMID: 37140166, 30586141); Not observed at significant frequency in large population cohorts (gnomAD); 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: 24686846, 30451293, 32015491, 31259407, Offin_2020_Abstract, 32155570, 34648949, 32172474, 32987645, 34193977, 36624550, 28393830, 36876055, 37140166, 30586141)

The variant is rare in gnomADv4 (14/1607628 alleles ; frequency : 0.00087%). Isoleucine 78 is an amino acid that seems very conserved in evolution except in zebrafish. The variant has been reported in an individual with multiple primary melanomas (PMID: 24686846), in several families with melanoma (PMID: 30586141_2018) and in an individual with 2 melanomas and thyroid cancer (PMID: 30451293_2019). This variant is located in the DNA binding domain of POT1 and was recently shown to impair the ability of POT1 to bind to telomeres (PMID:30586141_2018). The patient's phenotype and family history are compatible with the pathology associated with POT1 gene.

Variant interpreted as Uncertain significance and reported on 03-23-2018 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.