The NM_198253.2:c.3334C>A (p.Leu1112Met) missense variant in TERT is absent from large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_supporting).1 Multiple in silico tools predict a benign or neutral effect: REVEL score 0.155, BayesDel score -0.27587, and SpliceAI max delta 0.00 (BP4_supporting).2 This variant has been reported in ClinVar as a Variant of Uncertain Significance by two clinical laboratories (ClinVar ID 816668). No functional studies have been performed on this variant.3 The variant is a missense change at a residue that is not located in a mutational hotspot or well-established critical functional domain, and no alternate pathogenic missense variant at the same codon is known.4 Overall, the available evidence includes one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), yielding a net classification of Variant of Uncertain Significance under the generic ACMG/AMP 2015 framework.5
TERT
Final classification
VUS
PM2BP4
TERT
c.3334C>A
p.Leu1112Met
This variant
The NM_198253.2:c.3334C>A (p.Leu1112Met) missense variant in TERT is absent from large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_supporting).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
TERT c.3334C>A
PM2 + BP4
→
VUS
Gene diagram
· NM_198253.2 · variants mapped to exon structure
TERT
NM_198253.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the generic ACMG PM2 threshold (allele frequency < 0.1%). Absence from large population databases supports pathogenicity.
Variant absent from gnomAD v2.1 (0 alleles)gnomAD v4.1 (0 alleles)and gnomAD-Canada v1.0 (0 alleles).
✓
BP4
supporting
Benign
BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. Multiple in silico tools predict a benign or neutral effect: REVEL score 0.155 (below the 0.5 pathogenic threshold, borderline for the <0.15 benign threshold), BayesDel score -0.27587 (negative score favors benign), and SpliceAI max delta score 0.00 (predicts no splicing impact). Taken together, these computational predictions support a lack of deleterious effect.
REVEL 0.155 (borderline benign)BayesDel -0.27587 (benign)SpliceAI 0.00 (no splicing impact).
Assessed · not applied
· 19 not met · 0 not assessed
Pathogenic
PS1
PS1 requires a different nucleotide change at the same codon resulting in the same amino acid change that is already known to be pathogenic.
PS2
PS2 requires a de novo observation with both paternity and maternity confirmed.
PS3
PS3 requires well-established in vitro or in vivo functional studies supporting a damaging effect.
PS4
PS4 requires a statistically significant enrichment of the variant in affected individuals compared to controls.
PM1
PM1 requires the variant to be located in a mutational hotspot or critical, well-established functional domain without benign variation.
PM6
PM6 requires a de novo observation without confirmation of paternity and maternity.
PP1
PP1 requires co-segregation of the variant with disease in multiple affected family members.
PP2
PP2 requires the gene to have a low rate of benign missense variation and for missense variants to be a common mechanism of disease.
PP3
PP3 requires multiple lines of computational evidence supporting a deleterious effect on the gene or gene product.
PP4
PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
PP5
PP5 requires a reputable source to have reported the variant as pathogenic, but with evidence not available to the evaluating laboratory.
Benign
BA1
BA1 requires a minor allele frequency > 1% in a general population database.
BS1
BS1 requires a minor allele frequency > 0.3% in a general population database.
BS2
BS2 requires observation of the variant in a healthy adult in the homozygous state, or in the hemizygous/heterozygous state for a fully penetrant dominant disorder.
BS3
BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing.
BS4
BS4 requires lack of co-segregation with disease in multiple affected family members.
BP2
BP2 requires observation of the variant in trans with a known pathogenic variant for a fully penetrant dominant disorder, or in cis with a known pathogenic variant in any inheritance pattern.
BP5
BP5 requires the variant to be found in a case with an alternative molecular basis for disease.
BP6
BP6 requires a reputable source to report the variant as benign without access to the primary data.
N/A · 4
PVS1 · PM5 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 816668)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.155. BayesDel score = -0.27587.
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 4 PMIDs not cited in assessment
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
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR