Classification rationale

BA1BS1BP4 Benign

TERT c.3184G>A

The TERT NM_198253.2:c.3184G>A (p.Ala1062Thr) variant has been reported in ClinVar, where most submissions classify it as benign or likely benign.¹ This variant is common in population databases, with allele frequencies of 1.24601% in gnomAD v2.1 and 1.94967% in gnomAD v4.1, which are above the benign stand-alone threshold of 1.0% and above the BS1 threshold of 0.3%.² In silico prediction does not support a damaging effect, with REVEL 0.207, BayesDel -0.373519, and SpliceAI maximum delta score 0.01 predicting no significant splice impact.³

BA1 + BS1 + BP4 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 revelbayesdelspliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

This variant is common in population databases. The gnomAD v2.1 allele frequency is 1.24601% and the gnomAD v4.1 allele frequency is 1.94967%, both above the benign stand-alone threshold of 1.0%.

gnomAD v2.1 AF 0.0124601gnomAD v4.1 AF 0.0194967

gnomad_v2 ↗gnomad_v4 ↗

BS1 strong Benign

Population frequency is greater than expected for a pathogenic TERT germline variant. The gnomAD v2.1 allele frequency is 1.24601% and the gnomAD v4.1 allele frequency is 1.94967%, both above the BS1 threshold of 0.3%.

gnomAD v2.1 AF 0.0124601gnomAD v4.1 AF 0.0194967

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting Benign

Multiple computational results support a benign effect. REVEL is 0.207 and BayesDel is -0.373519, both favoring a tolerated missense change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01.

REVEL 0.207BayesDel -0.373519SpliceAI max delta 0.01

spliceai ↗

Assessed · not applied · 4 not met · 13 not assessed

Pathogenic

PS1 No evidence was identified that another nucleotide change causing the same amino acid substitution has already been established as pathogenic or likely pathogenic.

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.

PS3 Published TERT functional literature was identified, but the reviewed materials did not provide a well-established variant-specific functional assay result for p.(Ala1062Thr) that could be used to support a damaging effect.

PS4 Although this variant has been reported in disease literature and ClinVar, it is also common in population databases, with gnomAD v2.1 AF 1.24601% and gnomAD v4.1 AF 1.94967%, both well above the PM2 rarity threshold of 0.1%.

PM1 This variant does not lie in a statistically significant hotspot, and no well-established critical region without benign variation was identified for residue Ala1062 from the reviewed sources.

PM2 This variant is not absent or rare in population databases.

PM3 No evidence was identified for occurrence in trans with a pathogenic variant in a recessive disease context.

PM5 No reviewed evidence established a different pathogenic missense change at the same amino acid residue that could support PM5.

PM6 No assumed de novo occurrence without confirmed parentage 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 case-specific phenotype information was identified that is highly specific for a single genetic etiology and sufficient to support PP4.

Benign

BS2 This variant is observed in multiple homozygotes in gnomAD, but the reviewed materials did not provide gene-specific penetrance or phenotype context needed to determine whether BS2 should be applied for TERT-related disease.

BS3 Published TERT functional literature was identified, but the reviewed materials did not provide a well-established variant-specific functional assay result for p.(Ala1062Thr) demonstrating normal function that would support BS3.

BS4 No non-segregation data were identified for this variant.

BP2 No phase data were identified to determine whether this variant occurs in trans with a pathogenic variant for a dominant disorder or in cis with another variant.

BP5 No alternate molecular explanation for a specific reported phenotype was identified for the individual under evaluation.

N/A · 8 PVS1 · PM4 · PP2 · PP5 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.0194967; MAF= 1.94967%, 31441/1612636 alleles, homozygotes = 363) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0242779; MAF= 2.42779%, 28644/1179840 alleles, homozygotes = 340); grpmax FAF= 0.024042.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.0124601; MAF= 1.24601%, 3466/278168 alleles, homozygotes = 44) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0214947; MAF= 2.14947%, 2726/126822 alleles, homozygotes = 40); grpmax FAF= 0.0209994.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

1.9% · 31441 / 1,612,636
363 hom · FAF 2.4%

European (non-Finnish) 28644 / 1,179,840	2.4% 340 hom
Remaining individuals 1097 / 62,482	1.8% 12 hom
Amish 15 / 910	1.6% 1 hom
European (Finnish) 850 / 62,876	1.4% 7 hom
Admixed American 307 / 59,986	0.51%
African/African American 252 / 75,014	0.34% 1 hom
South Asian 211 / 91,052	0.23% 2 hom
Ashkenazi Jewish 59 / 29,578	0.2%
Middle Eastern 3 / 6,044	0.05%
East Asian 3 / 44,854	0.0067%

gnomAD v2.1

1.2% · 3466 / 278,168
44 hom · FAF 2.1%

European (non-Finnish) 2726 / 126,822	2.1% 40 hom
Remaining individuals 103 / 7,090	1.5% 1 hom
European (Finnish) 332 / 24,850	1.3% 1 hom
Admixed American 144 / 35,242	0.41%
African/African American 71 / 23,892	0.3%
Ashkenazi Jewish 25 / 10,256	0.24%
South Asian 64 / 30,562	0.21% 2 hom
East Asian 1 / 19,454	0.0051%

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (10 clinical laboratories) and as Likely benign (6 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely Benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.207. BayesDel score = -0.373519.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TERT is an enzyme that functions to maintain telomere length and genomic stability. The TERT promoter is frequently mutated in various cancer types.

OncoKB ↗

COSMIC

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; COSV57200744, n = 7 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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