NM_198253.2:c.26C>T (p.Ala9Val) in TERT is a missense variant absent from population databases (gnomAD v2.1 and v4.1, 0/1,349,032 alleles; PM2_supporting met).1 Multiple in silico predictors do not support a deleterious effect on the gene product: REVEL score 0.372, BayesDel score -0.166, and SpliceAI max delta 0.01 (BP4_supporting met).2 No variant-specific functional studies, case-control data, segregation data, or de novo observations have been reported for this variant. ClinVar classification is Uncertain Significance (1 clinical laboratory, criteria provided, single submitter). No expert panel review is available.3 With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is conflicting and insufficient to classify the variant as either pathogenic or benign.4 Overall classification: Uncertain Significance (VUS) per generic ACMG/AMP 2015 framework.5
TERT
Final classification
VUS
TERT c.26C>T · p.Ala9Val
TERT
NM_198253.2:c.26C>T (p.Ala9Val) in TERT is a missense variant absent from population databases (gnomAD v2.1 and v4.1, 0/1,349,032 alleles; PM2_supporting met).
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; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
TERT c.26C>T
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 · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_198253.2:c.26C>T is absent from gnomAD v2.1 exomes and gnomAD v4.1 (0/1,349,032 alleles), with an allele frequency well below the 0.1% threshold for PM2 application.
gnomAD v2.1: absent (0 alleles).gnomAD v4.1: 0/1349
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no deleterious effect: REVEL score 0.372 (below pathogenic threshold), BayesDel score -0.166 (negative/benign-leaning), and SpliceAI predicts no splice impact (max delta 0.01).
REVEL: 0.372 (<0.5 pathogenic threshold).BayesDel: -0.166 (benign-leaning).SpliceAI: max delta 0.01 (no splicing impact).
Assessed · not applied
Pathogenic
PS1
No evidence that an alternate nucleotide change at the same codon resulting in p.Ala9Val has been previously classified as pathogenic.
PS2
No de novo data available for NM_198253.2:c.26C>T.
PS3
No variant-specific functional studies identified for NM_198253.2:c.26C>T (p.Ala9Val).
PS4
No case-control studies or systematic patient ascertainment data are available for NM_198253.2:c.26C>T.
PM1
p.Ala9Val is located at the extreme N-terminus of TERT (position 9 of 1132 amino acids), outside of characterized critical functional domains (TEN domain, TRBD, RT, CTE).
PM6
No de novo observations have been reported for NM_198253.2:c.26C>T.
PP1
No family segregation data are available for NM_198253.2:c.26C>T.
PP2
No missense constraint score is available for TERT (HCI prior not supported for this gene).
PP3
In silico predictors do not support a deleterious effect: REVEL score 0.372 is below the typical pathogenic threshold (0.5), BayesDel score -0.166 is negative (benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.01).
PP4
No patient phenotype information is available to assess whether this variant was identified in a proband with a phenotype specific for TERT-related telomere biology disorders.
PP5
ClinVar classification for variant 2934760 is Uncertain Significance from a single clinical laboratory (criteria provided, single submitter).
Benign
BA1
Allele frequency is 0% in gnomAD v4.1 (0/1,349,032 alleles), well below the BA1 threshold of 1%.
BS1
Allele frequency is 0% in gnomAD, well below the BS1 threshold of 0.3%.
BS2
No data available on observation of this variant in healthy adult controls for a fully penetrant disorder.
BS3
No well-established functional studies demonstrate that NM_198253.2:c.26C>T has no damaging effect on protein function or splicing.
BS4
No segregation data are available to assess non-segregation of this variant with disease in affected families.
BP1
TERT is associated with disease through both loss-of-function and missense mechanisms; pathogenic missense variants in TERT are well-documented.
BP2
No data on observation of this variant in trans with a pathogenic variant in a fully penetrant dominant disorder.
BP5
No evidence that an alternate molecular basis for disease has been identified in a case carrying this variant.
BP6
ClinVar classification for variant 2934760 is Uncertain significance, not benign, from a single submitter (1-star).
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1349032 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/65678 alleles, homozygotes = 0).
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 / 1,349,032
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
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 (1 clinical laboratory). (ClinVarID = 2934760)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.372. BayesDel score = -0.166256.
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 · 1 PMID not cited in assessment