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TERTc.3334C>AUncertain significance
Print report
Variant interpretation report

TERT c.3334C>A, p.(Leu1112Met)

NM_198253.2:c.3334C>A NP_937983.2:p.(Leu1112Met) 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

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

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 benign; 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
0.000 maximum delta

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

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

2 Uncertain significance.

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.

26 criteria with recorded statuses: 2 met · 20 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

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).

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.

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.

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.

Met · 2

PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD v2.1 (0 alleles)
  • gnomAD v4.1 (0 alleles)
  • and gnomAD-Canada v1.0 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingBP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.155 (borderline benign)
  • BayesDel -0.27587 (benign)
  • SpliceAI 0.00 (no splicing impact).
Sources
revelbayesdelspliceai ↗

Not met · 20 · evaluated, threshold not reached

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. No such variant has been identified for codon 1112 of TERT. The PM5 candidate search found no same-residue comparator variants in ClinVar. Details ▾Hide ▴
Evidence considered
  • No pathogenic variant at the same codon (Leu1112) identified in ClinVar or the literature.
Sources
pm5_candidatesclinvar ↗
PS2 PS2 requires a de novo observation with both paternity and maternity confirmed. No de novo data for this variant were identified in ClinVar submissions, the literature, or any other source. Details ▾Hide ▴
Evidence considered
  • No de novo evidence available.
Still missing
  • No de novo testing data available.
Sources
clinvar ↗
PS3 PS3 requires well-established in vitro or in vivo functional studies supporting a damaging effect. No functional studies have been performed on this variant. The ClinVar submission from Labcorp Genetics (SCV001385529) explicitly states that functional predictions 'have not been confirmed by published functional studies.' OncoKB identified no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
  • No published functional studies identified for this variant. ClinVar SCV001385529 confirms absence of functional confirmation.
Still missing
  • No functional assay data exist for this variant.
Sources
clinvar ↗oncokb ↗
PS4 PS4 requires a statistically significant enrichment of the variant in affected individuals compared to controls. Two clinical laboratories have submitted this variant to ClinVar as a VUS, but no case-control data, cohort studies, or observational evidence demonstrating enrichment in affected individuals are available. The ClinVar-linked PMIDs (20301408, 20301779) are GeneReviews overviews that do not provide variant-specific case data. Details ▾Hide ▴
Evidence considered
  • Two ClinVar submissions as VUS but no case-control or cohort enrichment data.
Still missing
  • No case-control studies or cohort prevalence data available.
Sources
clinvar ↗PMID:20301408 ↗PMID:20301779 ↗
PM1 PM1 requires the variant to be located in a mutational hotspot or critical, well-established functional domain without benign variation. The p.Leu1112Met change lies in the C-terminal region of TERT. The hotspot analysis did not identify this residue as a statistically significant mutational hotspot, and no well-defined functional domain with an established clustering of pathogenic missense variants has been demonstrated at this position. Details ▾Hide ▴
Evidence considered
  • Residue 1112 is not in a statistically significant hotspot. No established critical domain clustering of pathogenic variants at this position.
PM6 PM6 requires a de novo observation without confirmation of paternity and maternity. No de novo data for this variant are available from any source. Details ▾Hide ▴
Evidence considered
  • No de novo evidence found.
Still missing
  • No de novo testing data available.
Sources
clinvar ↗
PP1 PP1 requires co-segregation of the variant with disease in multiple affected family members. No segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family studies or segregation data exist.
Sources
clinvar ↗
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. While missense variants are a recognized disease mechanism in TERT-related telomere biology disorders, no gene-level missense constraint metric (e.g., missense Z-score, HCI prior) is available for TERT to establish a low rate of benign missense variation. The HCI prior lookup returned no data for this gene. Details ▾Hide ▴
Evidence considered
  • No missense constraint metrics available for TERT. HCI prior not found.
Still missing
  • No missense Z-score or constraint data available for TERT.
Sources
pvs1_gene_context
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect on the gene or gene product. In silico predictions for this variant are not consistent with a deleterious effect: REVEL score 0.155 (below pathogenic threshold), BayesDel score -0.27587 (negative, favors benign), and SpliceAI max delta 0.00 (no splicing impact). The computational evidence does not support a pathogenic interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL 0.155 (benign-leaning)
  • BayesDel -0.27587 (benign)
  • SpliceAI 0.00 (no splicing impact).
Sources
revelbayesdelspliceai ↗
PP4 PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No patient-specific phenotype data are available for this case to support PP4. Details ▾Hide ▴
Evidence considered
  • No patient phenotype or family history data available.
Still missing
  • No patient phenotype information provided.
PP5 PP5 requires a reputable source to have reported the variant as pathogenic, but with evidence not available to the evaluating laboratory. ClinVar classifies this variant as Uncertain significance (2 submitters). Neither ClinVar submission asserts pathogenicity. The associated PMIDs (20301408, 20301779) are GeneReviews overviews of pulmonary fibrosis predisposition and dyskeratosis congenita that do not reference this specific variant. Details ▾Hide ▴
Evidence considered
  • ClinVar classification is VUS
  • not pathogenic. GeneReviews do not reference c.3334C>A.
Sources
clinvar ↗PMID:20301408 ↗PMID:20301779 ↗
BA1 BA1 requires a minor allele frequency > 1% in a general population database. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF = 0.0), so BA1 does not apply. Details ▾Hide ▴
Evidence considered
  • Variant absent from all gnomAD datasets
  • allele frequency 0.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 BS1 requires a minor allele frequency > 0.3% in a general population database. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF = 0.0), so BS1 does not apply. Details ▾Hide ▴
Evidence considered
  • Variant absent from all gnomAD datasets
  • allele frequency 0.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
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. The variant is absent from gnomAD, so no homozygous observations exist. The penetrance of TERT-related telomere biology disorders is not fully penetrant in a manner that would support BS2 from heterozygous observation alone. Details ▾Hide ▴
Evidence considered
  • Variant absent from population databases
  • no healthy homozygous observations.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS3 BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. No functional studies have been performed on this variant. The absence of studies does not constitute evidence that the variant is benign. Details ▾Hide ▴
Evidence considered
  • No functional studies exist for this variant.
Still missing
  • No functional assay data exist for this variant.
Sources
clinvar ↗oncokb ↗
BS4 BS4 requires lack of co-segregation with disease in multiple affected family members. No segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family segregation data exist.
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. No such observations exist for this variant. Details ▾Hide ▴
Evidence considered
  • No observations in trans or cis with a pathogenic variant.
BP5 BP5 requires the variant to be found in a case with an alternative molecular basis for disease. No such case data exist for this variant. Details ▾Hide ▴
Evidence considered
  • No observation 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. ClinVar classifies this variant as Uncertain Significance, not Benign. No source reports it as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar classification is VUS
  • not benign.
Sources
clinvar ↗
PS5 PS5 requires a reputable source to have reported the variant as pathogenic without the primary evidence being available to the evaluating laboratory. ClinVar classifies this variant as Uncertain Significance, not Pathogenic. No source reports it as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar classification is VUS
  • not pathogenic. GeneReviews do not reference this specific variant.
Sources
clinvar ↗PMID:20301408 ↗PMID:20301779 ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.3334C>A, p.Leu1112Met) in exon 16 of TERT. It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The variant bucket is 'other' per the PVS1 variant assessment framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not a null variant.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/APM5 requires a different pathogenic missense change at the same amino acid residue. The automated PM5 candidate search found zero same-residue comparator variants for Leu1112. No alternate pathogenic missense at codon 1112 is known. Details ▾Hide ▴
Evidence considered
  • No pathogenic missense comparators identified at p.Leu1112.
Sources
pm5_candidatesclinvar ↗
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. TERT-related telomere biology disorders (dyskeratosis congenita, pulmonary fibrosis, bone marrow failure) are caused by both truncating and missense variants. Pathogenic missense variants in TERT are well-documented in the literature. Therefore, BP1 does not apply. Details ▾Hide ▴
Evidence considered
  • TERT disease mechanism includes both truncating and missense pathogenic variants.
Sources
pvs1_gene_context
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact to the splice consensus sequence or the creation of a new splice site, and the nucleotide is not highly conserved. This is a missense variant (c.3334C>A, p.Leu1112Met), not a synonymous variant. BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • This is a missense variant
  • not a synonymous variant.

Identifiers

Gene
TERT
Transcript
NM_198253.2
Coding (HGVS c.)
NM_198253.2:c.3334C>A
Protein (HGVS p.)
NP_937983.2:p.(Leu1112Met)
GRCh38
chr5:1253793 G>T
GRCh37
chr5:1253908 G>T
ClinVar
816668

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 +430 bp
0.000
SpliceAI acceptor gainat -8 bp
0.000
SpliceAI donor lossat +305 bp
0.000
SpliceAI donor gainat +80 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
0.155
BayesDel
-0.276

How the predictions were used

BP4 SupportingBP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.155 (borderline benign)
  • BayesDel -0.27587 (benign)
  • SpliceAI 0.00 (no splicing impact).
Sources
revelbayesdelspliceai ↗
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect on the gene or gene product. In silico predictions for this variant are not consistent with a deleterious effect: REVEL score 0.155 (below pathogenic threshold), BayesDel score -0.27587 (negative, favors benign), and SpliceAI max delta 0.00 (no splicing impact). The computational evidence does not support a pathogenic interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL 0.155 (benign-leaning)
  • BayesDel -0.27587 (benign)
  • SpliceAI 0.00 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact to the splice consensus sequence or the creation of a new splice site, and the nucleotide is not highly conserved. This is a missense variant (c.3334C>A, p.Leu1112Met), not a synonymous variant. BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • This is a missense variant
  • not a synonymous variant.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.155. BayesDel score = -0.27587.

4 paper records 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

  • 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.
    Richards S et al. · 2015
    This is the ACMG/AMP 2015 standards and guidelines for sequence variant interpretation. It provides the framework for variant classification but does not discuss any specific variant including NM_198253.2:c.3334C>A.
    Does not name this variant
    PMID 25741868 ↗
  • Pulmonary Fibrosis Predisposition Overview.
    Adam MP et al. · 1993
    This is a GeneReviews overview of Pulmonary Fibrosis Predisposition, discussing genetic factors including TERT variants at the gene level. The specific variant NM_198253.2:c.3334C>A is not mentioned in this review.
    Does not name this variant
    PMID 20301408 ↗
  • Dyskeratosis Congenita and Related Telomere Biology Disorders.
    Adam MP et al. · 1993
    This is a GeneReviews overview of Dyskeratosis Congenita and Related Telomere Biology Disorders. It discusses TERT mutations at the gene level in the context of telomere biology disorders. The specific variant NM_198253.2:c.3334C>A is not mentioned in this review.
    Does not name this variant
    PMID 20301779 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    This is the Sherloc refinement of ACMG-AMP variant classification criteria. It describes a systematic framework for variant interpretation but does not discuss NM_198253.2:c.3334C>A or any specific TERT variant.
    Does not name this variant
    PMID 28492532 ↗

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 2 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 (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

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.