Classification rationale

BA1BS1BP7 Benign

TERT c.2031C>T

The TERT c.2031C>T (p.Gly677=) variant has been reported in ClinVar as benign by multiple clinical laboratories.¹ This variant is common in population databases, with allele frequencies above the BA1 benign threshold of 1% in gnomAD v2.1 (1.18898%), gnomAD v4.1 (1.12825%), and gnomAD-Canada (1.04812%).² This synonymous variant does not alter the encoded amino acid, and SpliceAI predicts no significant splice effect 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 Benign

Population frequency exceeds the benign stand-alone BA1 threshold of >1% in multiple datasets: gnomAD v2.1 AF is 1.18898%, gnomAD v4.1 AF is 1.12825%, and gnomAD-Canada AF is 1.04812%.

The variant is common in large population datasets and well above the 1% benign threshold.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BS1 strong Benign

Population frequency is also above the BS1 threshold of >0.3%, with gnomAD v2.1 AF 1.18898%, gnomAD v4.1 AF 1.12825%, and gnomAD-Canada AF 1.04812%.

All available population datasets show frequency above the strong benign threshold.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP7 supporting Benign

This is a synonymous variant with no predicted amino acid change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, supporting no expected effect on splicing.

Predicted protein consequence is p.(Gly677=)SpliceAI DS_AG 0.00DS_AL 0.00

spliceai ↗

Assessed · not applied

Pathogenic

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

PS3 No validated functional studies demonstrating a damaging effect of this specific variant were identified.

PS4 No case-control or case-enrichment data showing this variant is more common in affected individuals than in controls were identified.

PM1 This variant was not identified in a statistically significant mutational hotspot or other established critical functional region without benign variation.

PM2 Population frequency is far above the PM2 rarity threshold of <0.1%: gnomAD v2.1 AF is 1.18898%, gnomAD v4.1 AF is 1.12825%, and gnomAD-Canada AF is 1.04812%.

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

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: SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and missense predictors such as REVEL and BayesDel were not available for this synonymous change.

PP4 No phenotype data were identified that are sufficiently specific to a disease caused by TERT variants to support PP4.

PP5 PP5 was not used because no independent reputable-source pathogenic assertion was identified that should be applied as stand-alone evidence.

Benign

BS2 Although this variant is seen repeatedly in population databases, the available evidence does not directly establish observation in well-phenotyped unaffected individuals in a disease context suitable for BS2.

BS3 No well-established functional studies demonstrating a normal effect of this specific variant were identified.

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

BP2 No phase data were identified to show this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a way that would support BP2.

BP5 No alternate molecular diagnosis or other established cause was identified to explain a phenotype independently of this variant.

BP6 Although ClinVar contains multiple benign submissions, there is no expert-panel review or validated reputable-source evidence here that should be used as stand-alone BP6 evidence.

N/A · 8 PVS1 · PS1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP4

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.0112825; MAF= 1.12825%, 17575/1557728 alleles, homozygotes = 158) and has highest observed frequency in the Amish population (AF= 0.0789474; MAF= 7.89474%, 72/912 alleles, homozygotes = 2); grpmax FAF= 0.0466527.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.0118898; MAF= 1.18898%, 2256/189742 alleles, homozygotes = 24) and has highest observed frequency in the African/African American population (AF= 0.0505191; MAF= 5.05191%, 837/16568 alleles, homozygotes = 13); grpmax FAF= 0.0500696.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0104812; MAF= 1.04812%, 193/18414 alleles, homozygotes = 0) and has highest observed frequency in the afr population (AF= 0.0558824; grpmax FAF95= 0.0442897).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

1.1% · 17575 / 1,557,728
158 hom · FAF 4.7%

Amish 72 / 912	7.9% 2 hom
African/African American 3524 / 73,456	4.8% 74 hom
European (Finnish) 731 / 58,950	1.2% 2 hom
Middle Eastern 51 / 4,622	1.1%
Remaining individuals 616 / 60,308	1% 4 hom
European (non-Finnish) 11723 / 1,152,686	1% 65 hom
Admixed American 452 / 51,982	0.87% 1 hom
South Asian 342 / 84,538	0.4% 10 hom
Ashkenazi Jewish 56 / 28,718	0.19%
East Asian 8 / 41,556	0.019%

gnomAD v2.1

1.2% · 2256 / 189,742
24 hom · FAF 5%

African/African American 837 / 16,568	5.1% 13 hom
European (Finnish) 226 / 18,982	1.2% 1 hom
European (non-Finnish) 850 / 77,562	1.1% 5 hom
Remaining individuals 50 / 5,550	0.9% 1 hom
Admixed American 199 / 26,128	0.76%
South Asian 81 / 23,106	0.35% 4 hom
Ashkenazi Jewish 13 / 8,774	0.15%

+ 1 not observed (East Asian)

gnomAD Canada 🇨🇦

1% · 193 / 18,414
0 hom · FAF 4.4%

indel · split

African/African American 57 / 1,020	5.6%
Remaining individuals 13 / 1,138	1.1%
European (non-Finnish) 114 / 11,738	0.97%
Latino/Admixed American 4 / 838	0.48%
South Asian 4 / 1,360	0.29%
Ashkenazi Jewish 1 / 832	0.12%

+ 3 not observed (East Asian, European (Finnish), Middle Eastern)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (16 clinical laboratories). (ClinVarID = 227096)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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; COSV99721410, n = 10 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 ↗ 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

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

Re-run this variant?