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TERT
Final classification
Benign
TERT c.2097C>T · p.Ala699=
TERT

The TERT c.2097C>T (p.Ala699=) variant has been reported in ClinVar as benign.

Gene
TERT
Transcript
NM_198253.2
HGVS · transcript:coding
NM_198253.2:c.2097C>T
Consequence
N/A
GRCh38
chr5:1279324 G>A
GRCh37
chr5:1279439 G>A
Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP7 supporting benign; combination = 1 stand-alone benign, which maps to Benign. ▾
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP7 supporting benign; combination = 1 stand-alone benign, which maps to Benign.
Classification rationale
BA1BS1BP7 Benign
TERT c.2097C>T

The TERT c.2097C>T (p.Ala699=) variant has been reported in ClinVar as benign.1 This variant is common in population databases, with AF 1.11328% in gnomAD v2.1, AF 0.89897% in gnomAD v4.1, and AF 1.28122% in gnomAD-Canada; the highest observed East Asian frequencies are 8.10613% in gnomAD v2.1 and 5.10623% in gnomAD v4.1, which is above benign frequency thresholds.2 As a synonymous change, available in silico splicing evidence does not support RNA disruption; SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.3

BA1 + BS1 + BP7 → Benign
1 clinvar ↗
2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
3 spliceai ↗
Gene diagram · NM_198253.2 · variants mapped to exon structure
TERT NM_198253.2
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
Applied · 3
Strength Supporting Moderate Strong Very strong
✓
BA1 stand-alone review Benign
Population frequency is above the benign stand-alone threshold of 1%. This variant is present at AF 1.11328% in gnomAD v2.1 and AF 1.28122% in gnomAD-Canada, with much higher East Asian frequencies of 8.10613% in gnomAD v2.1 and 5.10623% in gnomAD v4.1.
gnomAD v2.1 total AF 1.11328%gnomAD v4.1 East Asian AF 5.10623%gnomAD-Canada total AF 1.28122%
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
✓
BS1 strong review Benign
Population frequency is above the strong benign threshold of 0.3%. This variant is present at AF 1.11328% in gnomAD v2.1, AF 0.89897% in gnomAD v4.1, and AF 1.28122% in gnomAD-Canada.
gnomAD v2.1 total AFgnomAD v4.1 total AFgnomAD-Canada total AF
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
✓
BP7 supporting review Benign
This is a synonymous variant, NP_937983.2:p.(Ala699=), and available splicing prediction does not support RNA disruption. SpliceAI shows a maximum delta score of 0.00, which is below a level suggesting splice impact.
synonymous consequenceSpliceAI max delta score 0.00
spliceai ↗
Assessed · not applied
Pathogenic
PS2 No confirmed de novo data were identified for this variant.
PS3 No well-established functional study demonstrating a damaging effect for this specific variant was identified.
PS4 Available evidence does not show enrichment of this variant in affected individuals over controls, and the variant is common in population databases, which argues against PS4.
PM1 This variant is not located in a demonstrated mutational hotspot or other established critical functional region without benign variation.
PM2 This variant is not absent from population databases; it is present at AF 1.11328% in gnomAD v2.1, AF 0.89897% in gnomAD v4.1, and AF 1.28122% in gnomAD-Canada, so PM2 is not met.
PM3 No data were identified showing this variant in trans with a pathogenic variant for a recessive disease mechanism.
PM6 No assumed de novo evidence was identified for this variant.
PP1 No segregation data were identified for this variant.
PP3 Available computational evidence does not support a deleterious effect.
PP4 No phenotype-specific evidence was identified linking this variant to a highly specific TERT-related clinical presentation in a way that supports PP4.
PP5 External database assertions alone were not used as independent pathogenic evidence for this criterion.
Benign
BS2 Although the variant is seen in many population samples, no disease-specific framework was identified establishing that observation in unaffected adults is sufficient for BS2 in TERT-related disease.
BS3 No well-established functional study demonstrating a benign effect for this specific variant was identified.
BS4 No non-segregation data were identified for this variant.
BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis for a recessive disorder.
BP5 No alternate molecular explanation was identified that would make this variant an incidental finding relative to a fully explained phenotype.
BP6 External benign assertions were not used as independent evidence for this criterion.
N/A · 8 PVS1 · PS1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP4
Research & evidence
Population frequency · supports benign
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00898971; MAF= 0.89897%, 14255/1585702 alleles, homozygotes = 169) and has highest observed frequency in the East Asian population (AF= 0.0510623; MAF= 5.10623%, 2216/43398 alleles, homozygotes = 91); grpmax FAF= 0.049291.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.0111328; MAF= 1.11328%, 2562/230130 alleles, homozygotes = 78) and has highest observed frequency in the East Asian population (AF= 0.0810613; MAF= 8.10613%, 1332/16432 alleles, homozygotes = 68); grpmax FAF= 0.0770165.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0128122; MAF= 1.28122%, 236/18420 alleles, homozygotes = 5) and has highest observed frequency in the eas population (AF= 0.064275; grpmax FAF95= 0.0533145).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.9% · 14255 / 1,585,702
169 hom · FAF 4.9%
East Asian
2216 / 43,398
5.1%
91 hom
Amish
12 / 912
1.3%
Remaining individuals
654 / 61,310
1.1%
13 hom
European (non-Finnish)
10046 / 1,168,282
0.86%
53 hom
Ashkenazi Jewish
209 / 29,092
0.72%
South Asian
562 / 87,012
0.65%
8 hom
European (Finnish)
213 / 60,676
0.35%
Admixed American
196 / 56,046
0.35%
4 hom
Middle Eastern
9 / 4,478
0.2%
African/African American
138 / 74,496
0.19%
gnomAD v2.1
1.1% · 2562 / 230,130
78 hom · FAF 7.7%
East Asian
1332 / 16,432
8.1%
68 hom
Remaining individuals
47 / 6,206
0.76%
European (non-Finnish)
764 / 101,172
0.76%
5 hom
Ashkenazi Jewish
67 / 9,352
0.72%
South Asian
152 / 25,940
0.59%
4 hom
European (Finnish)
62 / 20,672
0.3%
Admixed American
90 / 30,550
0.29%
1 hom
African/African American
48 / 19,806
0.24%
gnomAD Canada 🇨🇦
1.3% · 236 / 18,420
5 hom · FAF 5.3%
indel · split
European (Finnish)
1 / 8
12%
East Asian
86 / 1,338
6.4%
3 hom
Remaining individuals
16 / 1,138
1.4%
South Asian
13 / 1,362
0.95%
European (non-Finnish)
111 / 11,742
0.95%
2 hom
Latino/Admixed American
5 / 838
0.6%
Ashkenazi Jewish
4 / 832
0.48%
+ 2 not observed (African/African American, Middle Eastern)
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Benign (16 clinical laboratories). (ClinVarID = 39107)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57230878, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 9 PMIDs not cited in assessment
22138009 ↗ NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology. CLINVAR
24033266 ↗ A systematic approach to assessing the clinical significance of genetic variants. CLINVAR
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR
20301408 ↗ PMID:20301408 CLINVAR
20301779 ↗ Dyskeratosis Congenita and Related Telomere Biology Disorders. CLINVAR
20963938 ↗ CEBPA-Associated Familial Acute Myeloid Leukemia (AML). CLINVAR
21610750 ↗ Clinical utility gene card for: dyskeratosis congenita. CLINVAR
23970018 ↗ Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR