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TERTc.2509C>TUncertain significance
Print report
Variant interpretation report

TERT c.2509C>T, p.(Leu837Phe)

NM_198253.2:c.2509C>T NP_937983.2:p.(Leu837Phe) 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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_198253.2:c.2509C>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting PM2 at supporting strength under generic ACMG/AMP with an allele frequency of 0.0 in all population databases.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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; combination = 1 supporting, 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
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied 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
2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV99716414, n = 2 times).

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: 1 met · 21 not met · 1 not assessed · 6 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.2509C>T (p.Leu837Phe) is a rare missense variant in the TERT gene that is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).

This variant has been reported in ClinVar as a Variant of Uncertain Significance by a single clinical laboratory (Labcorp/Invitae, SCV003459151).

No variant-specific functional studies, case-control data, de novo observations, segregation data, or same-residue pathogenic comparators were identified for this variant.

In silico predictions are conflicting: REVEL predicts a deleterious effect (0.735), while BayesDel predicts a benign effect (0.123), and SpliceAI predicts no splicing impact (delta = 0.00).

TERT loss-of-function is an established disease mechanism for autosomal dominant dyskeratosis congenita and related telomere biology disorders, and both truncating and missense variants have been reported as pathogenic in the literature.

Applying generic ACMG/AMP 2015 classification rules (PMID:25741868), only one supporting criterion (PM2) is met, with no benign criteria met. This is insufficient to classify as Likely Pathogenic or Likely Benign, resulting in a final classification of Variant of Uncertain Significance (VUS).

Met · 1

PM2 SupportingNM_198253.2:c.2509C>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting PM2 at supporting strength under generic ACMG/AMP with an allele frequency of 0.0 in all population databases. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exome).
  • Absent from gnomAD v4.1 (exome).
  • Absent from gnomAD-Canada v1.0 (genome
  • AF=0.0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 21 · evaluated, threshold not reached

PS1 No pathogenic or likely pathogenic variant with the same amino acid change (p.Leu837Phe or another change at L837) was identified in ClinVar or the literature. No same-residue comparator exists to support PS1. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned zero same-residue pathogenic comparators
  • no ClinVar entry classifies an L837 variant as P/LP.
Still missing
  • No same-residue pathogenic comparator available.
Sources
pm5_candidates
PS2 No de novo observation (with confirmed maternity and paternity) was identified for NM_198253.2:c.2509C>T in the available evidence. Details ▾Hide ▴
Evidence considered
  • No de novo data found in ClinVar submissions
  • literature
  • or any other source.
Still missing
  • No de novo testing data available for this variant.
PS3 No variant-specific functional data were identified for NM_198253.2:c.2509C>T (p.Leu837Phe) in the literature or through OncoKB. OncoKB classifies the variant as Unknown Oncogenic Effect, and no publication with experimental functional characterization of this variant was retrieved. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional studies found in the literature.
Still missing
  • No functional characterization of p.Leu837Phe available. Telomerase activity assays or telomere length measurements in variant-bearing cells would be informative.
Sources
oncokb ↗
PS4 No case-control data or statistically significant enrichment of NM_198253.2:c.2509C>T in affected individuals over controls was identified. A single ClinVar submitter classifies the variant as Uncertain significance, and no publication provides variant-specific prevalence data. Details ▾Hide ▴
Evidence considered
  • ClinVar: single submitter (Labcorp/Invitae)
  • classification VUS
  • no case-control or cohort enrichment data available.
Still missing
  • No case-control or cohort study reporting this variant in affected individuals.
Sources
clinvar ↗
PM1 The variant p.Leu837Phe lies in the C-terminal region of TERT but is not located in a statistically significant mutational hotspot per cancerhotspots.org, and no literature was identified that specifically characterizes position 837 as lying within a well-characterized critical functional domain where missense variants are an established disease mechanism. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: residue not statistically significant
  • no domain-level functional characterization specific to position 837 identified in the literature.
Still missing
  • The C-terminal region of TERT is functionally important for processivity
  • literature characterizing domain-level constraints at this position was not retrieved but may exist.
PM5 No pathogenic or likely pathogenic missense variant at the same amino acid residue (p.Leu837) was identified in ClinVar. The PM5 candidate harvest returned zero same-residue comparators. Details ▾Hide ▴
Evidence considered
  • ClinVar same-residue search: zero candidate comparator variants at position 837 with P/LP classification.
Still missing
  • No known pathogenic missense at residue 837.
Sources
pm5_candidates
PM6 No de novo observation (without confirmed parentage) was identified for NM_198253.2:c.2509C>T in the available evidence. Details ▾Hide ▴
Evidence considered
  • No de novo data found.
Still missing
  • No de novo testing data available.
PP1 No co-segregation data with disease in multiple affected family members were identified for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No family studies or segregation analysis for this variant.
PP3 In silico predictions are conflicting: REVEL predicts a deleterious effect (score 0.735, above 0.5 threshold), but BayesDel predicts a benign effect (score 0.123, below the damaging threshold). SpliceAI predicts no splicing impact (max delta = 0.00). Multiple lines of computational support for a deleterious effect are not present; the conflict between REVEL and BayesDel precludes PP3 application. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.735 (damaging-leaning).
  • BayesDel score 0.123 (benign-leaning).
  • SpliceAI max delta 0.00 (no splice impact).
Still missing
  • Conflicting in silico predictions
  • no consensus across tools.
Sources
revelbayesdelspliceai ↗
PP4 No patient-specific phenotype or family history data highly specific for a TERT-related telomere biology disorder were available for this case. Details ▾Hide ▴
Evidence considered
  • No patient phenotype or clinical data available.
Still missing
  • Patient phenotype data not provided.
PP5 No reputable source classifies NM_198253.2:c.2509C>T as pathogenic. The single ClinVar submission classifies it as Uncertain significance. PMID:20301779 (GeneReviews on Dyskeratosis Congenita) is a general gene-level review and does not specifically classify this variant. PMID:28492532 (Sherloc) is a methodology paper and does not reference this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Uncertain significance (single submitter).
  • PMID:20301779: GeneReviews general review
  • does not classify or specifically mention this variant.
  • PMID:28492532: Methodology paper
  • does not reference this variant.
Sources
clinvar ↗PMID:20301779 ↗
BA1 NM_198253.2:c.2509C>T is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). Allele frequency of 0.0 is far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0.0 across all population databases
  • well below 1% BA1 cutoff.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 NM_198253.2:c.2509C>T is absent from all population databases. Allele frequency of 0.0 is below the 0.3% BS1 threshold for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0.0
  • below 0.3% BS1 cutoff.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No evidence that NM_198253.2:c.2509C>T has been observed in a healthy adult individual for a fully penetrant disorder. Population databases show zero observations. Details ▾Hide ▴
Evidence considered
  • No observation in healthy controls or unaffected adults.
Still missing
  • No control cohort data specific to this variant.
BS3 No well-established functional studies were identified that demonstrate NM_198253.2:c.2509C>T has no deleterious effect on protein function or splicing. No functional assay data exist for this variant. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no functional studies showing benign effect identified.
Still missing
  • No functional characterization of p.Leu837Phe available to demonstrate a benign effect.
Sources
oncokb ↗
BS4 No segregation data in affected families are available to demonstrate lack of co-segregation with disease. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No family studies for this variant.
BP1 While TERT loss-of-function is an established disease mechanism for telomere biology disorders, pathogenic missense variants in TERT are also well-documented in the literature (e.g., in dyskeratosis congenita and MDS). The gene does not primarily cause disease through truncating variants only; therefore BP1 does not apply to a TERT missense variant. Details ▾Hide ▴
Evidence considered
  • TERT has both truncating and missense pathogenic variants reported
  • BP1 requires a gene where primarily truncating variants cause disease.
Sources
pvs1_gene_context
BP2 No evidence that NM_198253.2:c.2509C>T has been observed in trans with a known dominant pathogenic variant for a fully penetrant disorder. Details ▾Hide ▴
Evidence considered
  • No trans-phase data available.
Still missing
  • No phase information or co-occurrence data with known pathogenic variants.
BP4 In silico predictions are conflicting: REVEL score of 0.735 suggests a deleterious effect, which contradicts the benign prediction from BayesDel (score 0.123). SpliceAI shows no splicing impact (delta = 0.00). BP4 requires multiple lines of computational evidence suggesting no impact on gene product; the REVEL score precludes this conclusion. Details ▾Hide ▴
Evidence considered
  • REVEL 0.735 (damaging prediction
  • contradicts BP4).
  • BayesDel 0.123 (benign-leaning).
  • SpliceAI delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP5 No evidence that NM_198253.2:c.2509C>T was found in a case with an alternative molecular basis for disease. Details ▾Hide ▴
Evidence considered
  • No data on alternate molecular diagnoses in individuals carrying this variant.
Still missing
  • No alternate molecular diagnosis data available.
BP6 No reputable source classifies NM_198253.2:c.2509C>T as benign. ClinVar classification is Uncertain significance. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance
  • no source reports this variant as benign.
Sources
clinvar ↗

Not assessed · 1 · no assessment recorded

PP2 PP2 requires evidence that TERT has a low rate of benign missense variation (e.g., high missense Z-score or constraint metric). The HCI prior was not available for TERT (gene not supported), and no alternative missense constraint metric was retrieved. This criterion cannot be adjudicated without constraint data. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for TERT
  • no missense constraint metric retrieved.
Still missing
  • Missense constraint metric (e.g.
  • gnomAD missense Z-score
  • HCI prior) needed to assess PP2.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_198253.2:c.2509C>T is a missense variant (p.Leu837Phe) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a null variant eligible for PVS1 under generic ACMG/AMP.
Sources
pvs1_generic_framework ↗
PM3 N/ASkipped per instruction. Recessive disorder trans-phase observation: no such data available for this variant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASkipped per instruction. Protein length change: variant is a missense substitution, not an in-frame indel or stop-loss. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ASkipped per instruction. In-frame indels in non-repeat regions: variant is a substitution, not applicable. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_198253.2:c.2509C>T is a missense variant (p.Leu837Phe), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is restricted to synonymous/intronic variants.
PS5 N/APS5 is not a criterion defined in the generic ACMG/AMP 2015 guidelines (PMID:25741868). No CSPEC/VCEP framework with an operative PS5 rule was available for TERT. Details ▾Hide ▴
Evidence considered
  • Not a defined criterion in the governing classification framework.

Identifiers

Gene
TERT
Transcript
NM_198253.2
Coding (HGVS c.)
NM_198253.2:c.2509C>T
Protein (HGVS p.)
NP_937983.2:p.(Leu837Phe)
GRCh38
chr5:1268593 G>A
GRCh37
chr5:1268708 G>A
ClinVar
2151563
COSMIC
COSV99716414

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 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +283 bp
0.000
SpliceAI acceptor gainat +40 bp
0.000
SpliceAI donor lossat -389 bp
0.000
SpliceAI donor gainat +229 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.735
BayesDel
0.123

How the predictions were used

PP3 In silico predictions are conflicting: REVEL predicts a deleterious effect (score 0.735, above 0.5 threshold), but BayesDel predicts a benign effect (score 0.123, below the damaging threshold). SpliceAI predicts no splicing impact (max delta = 0.00). Multiple lines of computational support for a deleterious effect are not present; the conflict between REVEL and BayesDel precludes PP3 application. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.735 (damaging-leaning).
  • BayesDel score 0.123 (benign-leaning).
  • SpliceAI max delta 0.00 (no splice impact).
Still missing
  • Conflicting in silico predictions
  • no consensus across tools.
Sources
revelbayesdelspliceai ↗
BP4 In silico predictions are conflicting: REVEL score of 0.735 suggests a deleterious effect, which contradicts the benign prediction from BayesDel (score 0.123). SpliceAI shows no splicing impact (delta = 0.00). BP4 requires multiple lines of computational evidence suggesting no impact on gene product; the REVEL score precludes this conclusion. Details ▾Hide ▴
Evidence considered
  • REVEL 0.735 (damaging prediction
  • contradicts BP4).
  • BayesDel 0.123 (benign-leaning).
  • SpliceAI delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_198253.2:c.2509C>T is a missense variant (p.Leu837Phe), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is restricted to synonymous/intronic variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.735. BayesDel score = 0.123435.

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 providing a general overview of Dyskeratosis Congenita and Related Telomere Biology Disorders, including TERT-associated disease. NM_198253.2:c.2509C>T (p.Leu837Phe) was not specifically mentioned or classified in this review.
    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 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 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

Absent from gnomAD v4.1.

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 = 2151563)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.735. BayesDel score = 0.123435.

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 previously been reported in somatic cancers (COSMIC; COSV99716414, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.