Classification rationale

BA1BP4 Benign

TERT c.1950+10C>T

The TERT c.1950+10C>T (p.?) variant has been reported in ClinVar as Benign by 14 clinical laboratories.¹ This variant is common in population databases, with allele frequencies of 1.36750% in gnomAD v2.1 and 1.21665% in gnomAD v4.1, both above the 1% BA1 threshold, and reaches approximately 4.14% to 4.07% in the Finnish population.² In silico splice prediction does not support a clinically meaningful splicing effect, with SpliceAI showing a maximum delta score of 0.07.³

BA1 + BP4 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

Gene diagram · NM_198253.2 · variants mapped to exon structure

TERT NM_198253.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 16 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

BA1 stand-alone review Benign

Population frequency exceeds the generic BA1 threshold of 1%. This variant is present at 1.36750% in gnomAD v2.1 and 1.21665% in gnomAD v4.1, with the highest observed frequency in the Finnish population at about 4.14% and 4.07%, respectively, which strongly supports a benign interpretation.

gnomAD v2.1 total AF 0.013674971687429219Finnish AF 0.04140127388535031649 homozygotes.

gnomad_v2 ↗gnomad_v4 ↗

✓

BP4 supporting review Benign

Available computational evidence supports no meaningful impact on splicing. SpliceAI predicts no significant splice effect, with a maximum delta score of 0.07, which is below commonly used thresholds for splice disruption.

SpliceAI max delta score 0.07.

spliceai ↗

Assessed · not applied

Pathogenic

PS2 No confirmed de novo data with verified parentage were identified for this variant.

PS3 No validated functional study of this exact variant showing a damaging effect was identified.

PS4 Available evidence does not show that this variant is enriched in affected individuals compared with controls.

PM2 This variant is not absent from population databases; instead, it is common in gnomAD with total allele frequencies of 1.36750% in v2.1 and 1.21665% in v4.1, which is far above the generic PM2 rarity threshold of 0.1%.

PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease setting.

PM6 No assumed de novo occurrence data were identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a damaging effect on splicing.

PP4 No phenotype data specific enough to support a highly characteristic TERT-related presentation for this variant were identified.

PP5 PP5 was not used because primary supporting evidence for a pathogenic classification was not identified, and this criterion is not relied on here.

Benign

BS2 Although this variant is observed many times in population databases, no dataset-specific healthy adult phenotyping framework was identified to support independent BS2 application.

BS3 No validated functional study of this exact variant showing a normal or no-impact effect was identified.

BS4 No family data were identified showing lack of segregation with disease.

BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.

BP5 No independent alternate molecular explanation for a reported phenotype was identified.

BP6 Although ClinVar contains multiple benign submissions, BP6 was not separately applied because the benign classification itself is not treated here as independent criterion-level evidence beyond the underlying population and computational findings.

N/A · 10 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BS1 · BP1 · BP3 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.0121665; MAF= 1.21665%, 19637/1614020 alleles, homozygotes = 187) and has highest observed frequency in the European (Finnish) population (AF= 0.0407496; MAF= 4.07496%, 2603/63878 alleles, homozygotes = 65); grpmax FAF= 0.023973.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.013675; MAF= 1.36750%, 3864/282560 alleles, homozygotes = 49) and has highest observed frequency in the European (Finnish) population (AF= 0.0414013; MAF= 4.14013%, 1040/25120 alleles, homozygotes = 22); grpmax FAF= 0.0239814.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0109168; MAF= 1.09168%, 201/18412 alleles, homozygotes = 1) and has highest observed frequency in the afr population (AF= 0.0205882; grpmax FAF95= 0.013796).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

1.2% · 19637 / 1,614,020
187 hom · FAF 2.4%

European (Finnish) 2603 / 63,878	4.1% 65 hom
African/African American 1870 / 75,060	2.5% 25 hom
Ashkenazi Jewish 707 / 29,606	2.4% 9 hom
Remaining individuals 754 / 62,508	1.2% 4 hom
European (non-Finnish) 12934 / 1,179,994	1.1% 73 hom
Middle Eastern 66 / 6,060	1.1%
Admixed American 466 / 60,028	0.78% 3 hom
South Asian 237 / 91,086	0.26% 8 hom

+ 2 not observed (Amish, East Asian)

gnomAD v2.1

1.4% · 3864 / 282,560
49 hom · FAF 2.4%

European (Finnish) 1040 / 25,120	4.1% 22 hom
African/African American 618 / 24,952	2.5% 8 hom
Ashkenazi Jewish 230 / 10,370	2.2% 2 hom
Remaining individuals 105 / 7,226	1.5%
European (non-Finnish) 1544 / 128,898	1.2% 10 hom
Admixed American 251 / 35,426	0.71% 2 hom
South Asian 76 / 30,616	0.25% 5 hom

+ 1 not observed (East Asian)

gnomAD Canada 🇨🇦

1.1% · 201 / 18,412
1 hom · FAF 1.4%

indel · split

European (Finnish) 2 / 8	25%
Ashkenazi Jewish 19 / 832	2.3% 1 hom
Middle Eastern 3 / 144	2.1%
African/African American 21 / 1,020	2.1%
Remaining individuals 15 / 1,138	1.3%
European (non-Finnish) 129 / 11,732	1.1%
Latino/Admixed American 8 / 838	0.95%
South Asian 4 / 1,362	0.29%

+ 1 not observed (East Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (14 clinical laboratories). (ClinVarID = 227097)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV57245267, n = 8 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

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 ↗ Pulmonary Fibrosis Predisposition Overview. CLINVAR

20301779 ↗ Dyskeratosis Congenita and Related Telomere Biology Disorders. CLINVAR

20963938 ↗ CEBPA-Associated Familial Acute Myeloid Leukemia (AML). CLINVAR

23970018 ↗ Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. CLINVAR

32171751 ↗ Acute myeloid leukaemia 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

Re-run this variant?