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 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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