ClinVar Genomic variation as it relates to human health

This variant occurs in a non-coding region of the TERT gene. It does not change the encoded amino acid sequence of the TERT protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been reported in two families with melanoma, and was shown to segregate with disease in these families (PMID: 23348503, 26433962). However, affected family members also had additional primary cancers such as ovarian cancer, bladder cancer, and basal cell carcinoma (PMID: 23348503, 26433962). This variant is also known as -57T>G. ClinVar contains an entry for this variant (Variation ID: 242210). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant is located in the TERT promoter region and creates new binding motifs for transcription factors, Ets and TCFs (PMID: 23348503). Experimental studies have shown that this variant affects promoter activity and transcription in vitro (PMID: 23348503, 31395865). While this variant did not increase TERT mRNA levels in human pluripotent stem cells (hESCs), it affected several normal TERT protein functions in vitro and in vivo (PMID: 26194807). However, the clinical significance of this data is uncertain. While there are association studies on TERT non-coding variants with various cancer risk (PMID: 23535731, 22037553, 23066086, 20871597), the current clinical and genetic evidence is not sufficient to establish whether TERT is causative for melanoma. 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.

DNA sequence analysis of the TERT gene demonstrated a sequence change in the 5 prime untranslated region, c.-57A>C. This pathogenic sequence change has previously been described in a large melanoma family (PMID: 23348503), and has been shown to create a transcription factor binding motif in the promoter region that results in an increased expression of TERT (Chiba K, et al, 2015; PMID: 23348503). This pathogenic sequence change has also been described as a somatic mutation in patients with myelodysplastic syndrome, bladder cancer and melanoma (Caterina Matteucci, et al., 2013; PMIDs: 24569790, 24101484). Somatic, pathogenic variants in the promoter region of the TERT gene, leading to increased telomerase activity, including the c.-57A>C change, have been reported in patients with pathogenic TERT mutations and telomere biology disorders including idiopathic pulmonary fibrosis and aplastic anemia (Gutierrez-Rodrigues et al., 2018 and Maryoung et al., 2017).

The c.-57A>C variant is located in the 5' untranslated region (5’ UTR) of the TERT gene. This variant results from an A to C substitution 57 bases upstream from the first translated codon. This variant has been reported in two melanoma-prone families in conjunction with a common TERT promoter variant, c.-246G>A (Horn S et al. Science, 2013 Feb;339:959-61; Harland M et al. Fam. Cancer, 2016 Jan;15:139-44). Functional studies have shown that this variant leads to increased TERT promoter activity (Horn S et al. Science, 2013 Feb;339:959-61; Kircher M et al. Nat Commun, 2019 08;10:3583), increased TERT mRNA levels, increased telomerase activity and increased telomere length (Chiba K et al. Elife, 2015 Jul;4; Chiba K et al. Science, 2017 09;357:1416-1420). However, another study did not find a difference in telomere length in individuals carrying c.-57A>C as compared to non-carriers with history of melanoma (Harland M et al. Fam. Cancer, 2016 Jan;15:139-44). This nucleotide position is poorly conserved in available vertebrate species. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.

Describes a nucleotide substitution 57 base pairs upstream of the ATG translational start site in the TERT promoter region; Observed segregating with disease in two families with multiple individuals with melanoma and some with various other cancers including ovarian cancer, bladder cancer, and basal cell carcinoma; however, an unaffected individual in one of the families was also found to carry this variant (PMID: 23348503, 26433962); Published in vitro and in vivo functional studies suggest a damaging effect: increased mRNA expression, TERT activity, and telomere length, as well as creation of a new ETS binding motif (PMID: 26194807, 31395865, 37918959); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26194807, 24569790, 24101484, Matteucci2013[article], 28192371, 23348503, 30523342, 30203894, 26433962, 31395865, 36636687, 28818973, 37918959, 35903534, 36810441)