0%
TERTc.26C>TUncertain significance
Print report
Variant interpretation report

TERT c.26C>T, p.(Ala9Val)

NM_198253.2:c.26C>T NP_937983.2:p.(Ala9Val) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About TERT

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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).

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 20 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

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).

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.

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.

Overall classification: Uncertain Significance (VUS) per generic ACMG/AMP 2015 framework.

Met · 2

PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent (0 alleles).
  • gnomAD v4.1: 0/1
  • 349
  • 032 alleles
  • AF=0.00000%.
  • gnomAD-Canada v1.0: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.372 (<0.5 pathogenic threshold).
  • BayesDel: -0.166 (benign-leaning).
  • SpliceAI: max delta 0.01 (no splicing impact).
Sources
revelbayesdelspliceai ↗

Not met · 20 · evaluated, threshold not reached

PS1 No evidence that an alternate nucleotide change at the same codon resulting in p.Ala9Val has been previously classified as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar variation 2934760 contains only this single nucleotide substitution at codon 9
  • no alternative nucleotide changes at this codon are reported as pathogenic.
Still missing
  • No alternate nucleotide changes at codon 9 identified.
Sources
clinvar ↗
PS2 No de novo data available for NM_198253.2:c.26C>T. Details ▾Hide ▴
Evidence considered
  • No de novo observations identified in ClinVar or the literature.
Still missing
  • No parental testing data available.
PS3 No variant-specific functional studies identified for NM_198253.2:c.26C>T (p.Ala9Val). OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB: no variant-specific functional evidence identified.
  • No published functional studies of p.Ala9Val found in literature review.
Still missing
  • No telomerase activity assay or telomere length data available for this specific variant.
Sources
oncokb ↗
PS4 No case-control studies or systematic patient ascertainment data are available for NM_198253.2:c.26C>T. The variant has been reported in ClinVar as a VUS from a single clinical laboratory without accompanying phenotype data. Details ▾Hide ▴
Evidence considered
  • ClinVar: single submitter (Labcorp/Invitae)
  • classification VUS
  • no aggregated case data.
  • No cohort studies or case series identifying this variant in affected individuals identified.
Still missing
  • No proband counts or case-control data.
Sources
clinvar ↗
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). Residue is not a statistically significant hotspot at cancerhotspots.org. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: residue not significant.
  • Position 9 lies in the N-terminal region preceding known structured functional domains.
Still missing
  • No functional domain characterization covering TERT residues 1-50.
PM6 No de novo observations have been reported for NM_198253.2:c.26C>T. Details ▾Hide ▴
Evidence considered
  • No de novo data found in ClinVar or literature.
Still missing
  • No parental testing data.
PP1 No family segregation data are available for NM_198253.2:c.26C>T. Details ▾Hide ▴
Evidence considered
  • No segregation analysis reported for this variant.
Still missing
  • No family studies or co-segregation data.
PP2 No missense constraint score is available for TERT (HCI prior not supported for this gene). Without evidence of a low rate of benign missense variation, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
  • HCI prior: not available for TERT.
Still missing
  • Missense Z-score or constraint metric unavailable for TERT.
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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.372 (below pathogenic threshold of 0.5).
  • BayesDel: -0.166 (benign-leaning).
  • SpliceAI: max delta 0.01 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
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. Details ▾Hide ▴
Evidence considered
  • No proband phenotype data provided for this case.
Still missing
  • Patient phenotype not available.
PP5 ClinVar classification for variant 2934760 is Uncertain Significance from a single clinical laboratory (criteria provided, single submitter). PP5 requires a pathogenic classification from a reputable source (≥3-star expert panel) — this submission does not meet that threshold. Details ▾Hide ▴
Evidence considered
  • ClinVar ID 2934760: VUS
  • single submitter (Labcorp/Invitae)
  • 1-star review status.
Sources
clinvar ↗
BA1 Allele frequency is 0% in gnomAD v4.1 (0/1,349,032 alleles), well below the BA1 threshold of 1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF = 0.00000%
  • 0/1
  • 349
  • 032 alleles.
Sources
gnomad_v4 ↗
BS1 Allele frequency is 0% in gnomAD, well below the BS1 threshold of 0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF = 0.00000%
  • 0/1
  • 349
  • 032 alleles.
Sources
gnomad_v4 ↗
BS2 No data available on observation of this variant in healthy adult controls for a fully penetrant disorder. Details ▾Hide ▴
Evidence considered
  • No healthy control observation data available.
Still missing
  • No population screening or control cohort data for this variant.
BS3 No well-established functional studies demonstrate that NM_198253.2:c.26C>T has no damaging effect on protein function or splicing. Details ▾Hide ▴
Evidence considered
  • No functional studies of this variant identified.
Still missing
  • No telomerase activity or telomere length data for p.Ala9Val.
BS4 No segregation data are available to assess non-segregation of this variant with disease in affected families. Details ▾Hide ▴
Evidence considered
  • No family studies or non-segregation data.
Still missing
  • No segregation analysis available.
BP1 TERT is associated with disease through both loss-of-function and missense mechanisms; pathogenic missense variants in TERT are well-documented. BP1 is reserved for genes where only truncating variants cause disease. Details ▾Hide ▴
Evidence considered
  • TERT has pathogenic missense variants associated with dyskeratosis congenita
  • MDS
  • and telomere biology disorders.
  • PVS1 gene gate established LoF mechanism
  • but missense variants are also a known disease mechanism in TERT.
Sources
pvs1_gene_context
BP2 No data on observation of this variant in trans with a pathogenic variant in a fully penetrant dominant disorder. Additionally, TERT-related disorders are primarily autosomal dominant. Details ▾Hide ▴
Evidence considered
  • No trans data available.
  • TERT telomere biology disorders are autosomal dominant.
BP5 No evidence that an alternate molecular basis for disease has been identified in a case carrying this variant. Details ▾Hide ▴
Evidence considered
  • No alternate molecular diagnosis data available.
Still missing
  • No data on alternative genetic findings in carriers.
BP6 ClinVar classification for variant 2934760 is Uncertain significance, not benign, from a single submitter (1-star). BP6 requires a benign classification from a reputable source (≥3-star expert panel). Details ▾Hide ▴
Evidence considered
  • ClinVar ID 2934760: VUS
  • single submitter (Labcorp/Invitae)
  • 1-star review status.
Sources
clinvar ↗
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_198253.2:c.26C>T is a missense variant (p.Ala9Val); it does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a predicted null variant.
  • PVS1 gene gate is eligible for TERT
  • but variant does not qualify for PVS1 strength assignment.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders where a variant is observed in trans with a pathogenic variant; TERT-related telomere biology disorders are autosomal dominant. Details ▾Hide ▴
Evidence considered
  • TERT disorders are autosomal dominant.
PM4 N/APM4 applies to protein length changes (in-frame deletions/insertions, stop-loss); NM_198253.2:c.26C>T is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not a protein length-altering variant.
PM5 N/ANo pathogenic comparator variants at the same codon (Ala9) were identified; PM5 candidate search returned zero same-residue candidates. Details ▾Hide ▴
Evidence considered
  • Zero same-residue pathogenic comparator variants identified in ClinVar.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame indels in repetitive regions; NM_198253.2:c.26C>T is a substitution variant. Details ▾Hide ▴
Evidence considered
  • Substitution variant
  • not an in-frame indel.
BP7 N/ANM_198253.2:c.26C>T is a missense variant (p.Ala9Val), not a silent/synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution (c.26C>T results in p.Ala9Val).
PS5 N/APS5 is not a defined criterion in the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868); no VCEP/CSPEC-specific PS5 rule exists for TERT. Details ▾Hide ▴
Evidence considered
  • Not applicable under generic ACMG/AMP 2015 framework.
Sources
generic_acmg_combination_rules

Identifiers

Gene
TERT
Transcript
NM_198253.2
Coding (HGVS c.)
NM_198253.2:c.26C>T
Protein (HGVS p.)
NP_937983.2:p.(Ala9Val)
GRCh38
chr5:1294964 G>A
GRCh37
chr5:1295079 G>A
ClinVar
2934760

Gene diagram

Every interpreted variant in TERT, mapped onto the exon structure of NM_198253.2. Select a row to find it on the plot.

TERTNM_198253.2
Fetching transcript structure from UCSC…
gnomAD v4.1 0 / 1,349,032 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,349,032 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -298 bp
0.000
SpliceAI acceptor gainat -273 bp
0.000
SpliceAI donor lossat -1 bp
0.000
SpliceAI donor gainat -34 bp
0.010
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.372
BayesDel
-0.166

How the predictions were used

BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.372 (<0.5 pathogenic threshold).
  • BayesDel: -0.166 (benign-leaning).
  • SpliceAI: max delta 0.01 (no splicing impact).
Sources
revelbayesdelspliceai ↗
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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.372 (below pathogenic threshold of 0.5).
  • BayesDel: -0.166 (benign-leaning).
  • SpliceAI: max delta 0.01 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_198253.2:c.26C>T is a missense variant (p.Ala9Val), not a silent/synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution (c.26C>T results in p.Ala9Val).

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.372. BayesDel score = -0.166256.

1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Dyskeratosis Congenita and Related Telomere Biology Disorders.
    Adam MP et al. · 1993
    GeneReviews chapter on Dyskeratosis Congenita and Related Telomere Biology Disorders, providing a general clinical overview of TERT-related disease. NM_198253.2:c.26C>T (p.Ala9Val) was not identified in this publication.
    Does not name this variant
    PMID 20301779 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 0 / 1,349,032 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar 1 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.