5-1295046-T-G

Variant names:

• chr5-1295046-T-G
• rs878855297
• NM_198253.3:c.-57A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The NM_198253.3(TERT):​c.-57A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000369 in 1,165,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000055 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: TERT NM_198253.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5 O:2
• Conservation: PhyloP100: -3.21
• Publications: 45 publications found

Genes affected

TERT (HGNC:11730): (telomerase reverse transcriptase) Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component which serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis. Studies in mouse suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. Alternatively spliced variants encoding different isoforms of telomerase reverse transcriptase have been identified; the full-length sequence of some variants has not been determined. Alternative splicing at this locus is thought to be one mechanism of regulation of telomerase activity. [provided by RefSeq, Jul 2008]

TERT Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyskeratosis congenita, autosomal dominant 2

  Inheritance: AR, AD, SD, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma, cutaneous malignant, susceptibility to, 9

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000300381 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP5: Variant 5-1295046-T-G is Pathogenic according to our data. Variant chr5-1295046-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242210.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198253.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	NM_198253.3	MANE Select	c.-57A>C		5_prime_UTR	Exon 1 of 16	NP_937983.2
	TERT	NR_149162.3		n.23A>C		non_coding_transcript_exon	Exon 1 of 13
	TERT	NR_149163.3		n.23A>C		non_coding_transcript_exon	Exon 1 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.-57A>C		5_prime_UTR	Exon 1 of 16	ENSP00000309572.5
	TERT	ENST00000656021.1		n.-57A>C		non_coding_transcript_exon	Exon 1 of 17	ENSP00000499759.1
	TERT	ENST00000656021.1		n.-57A>C		5_prime_UTR	Exon 1 of 17	ENSP00000499759.1

Frequencies

GnomAD3 genomes AF: 0.0000551 AC: 8 AN: 145306 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000407

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000896

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000343 AC: 35 AN: 1020424 Hom.: 0 Cov.: 16 AF XY: 0.0000553 AC XY: 27 AN XY: 488222

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21442

American (AMR) AF: 0.00 AC: 0 AN: 8446

Ashkenazi Jewish (ASJ) AF: 0.0000698 AC: 1 AN: 14336

East Asian (EAS) AF: 0.00 AC: 0 AN: 26416

South Asian (SAS) AF: 0.00 AC: 0 AN: 24452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2862

European-Non Finnish (NFE) AF: 0.0000373 AC: 32 AN: 857702

Other (OTH) AF: 0.0000474 AC: 2 AN: 42160

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000222045), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000551 AC: 8 AN: 145306 Hom.: 0 Cov.: 34 AF XY: 0.0000853 AC XY: 6 AN XY: 70364

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 38486

American (AMR) AF: 0.00 AC: 0 AN: 14474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.000407 AC: 2 AN: 4910

South Asian (SAS) AF: 0.00 AC: 0 AN: 4692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000896 AC: 6 AN: 66998

Other (OTH) AF: 0.00 AC: 0 AN: 2002

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000257311), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3

Nov 07, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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); Located in a regulatory region; in the absence of functional studies, the actual effect of this sequence change is unknown; 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)

Feb 24, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

Mar 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 16, 2024

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dyskeratosis congenita, autosomal dominant 2 Pathogenic:1

Mar 03, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Malignant tumor of urinary bladder Pathogenic:1

Laboratory of Urology, Hospital Clinic de Barcelona

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 gene product 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.

Dyskeratosis congenita Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Melanoma, cutaneous malignant, susceptibility to, 9 Other:1

Feb 22, 2013

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.4
DANN	Benign	0.30
PhyloP100		-3.2
PromoterAI		0.86	Over-expression
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs878855297; hg19: chr5-1295161; COSMIC: COSV57196893; COSMIC: COSV57196893;