0%
TERTc.899G>AUncertain significance
Print report
Variant interpretation report

TERT c.899G>A, p.(Gly300Asp)

NM_198253.2:c.899G>A NP_937983.2:p.(Gly300Asp) 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
PM2Moderate
PM2 · moderate

NM_198253.2:c.899G>A is absent from population databases. In gnomAD v4.1, the variant has 0 alleles across 1,571,010 total alleles (AF=0.00%), meeting the PM2 threshold for absence in population controls (AF < 0.1%).

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 moderate; combination = 1 moderate, 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
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.

27 criteria with recorded statuses: 1 met · 21 not met · 1 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_198253.2:c.899G>A (p.Gly300Asp) is a rare missense variant in TERT that is absent from population databases, with 0 alleles observed across 1,571,010 alleles in gnomAD v4.1, meeting PM2 (moderate) criterion.

This variant has been reported in ClinVar as Uncertain Significance by a single clinical laboratory (Variation ID 2937435; Labcorp Genetics). The classification is based on 1-star review status and does not meet the 3-star expert panel threshold for PP5 or BP6.

In silico predictors are inconclusive: REVEL (0.283) is intermediate, BayesDel (-0.187) is marginally in the benign direction, and SpliceAI predicts no splicing impact (max delta 0.00). No consensus supports either pathogenicity (PP3) or benignity (BP4).

No functional studies (PS3/BS3), case-control data (PS4), de novo observations (PS2/PM6), co-segregation data (PP1/BS4), or same-residue pathogenic comparators (PM5/PS1) are available for this variant.

The variant is a missense substitution and does not qualify for PVS1 null-variant assessment.

Based on the available evidence, this variant meets only one moderate pathogenicity criterion (PM2). Under the ACMG/AMP 2015 scoring framework, this alone is insufficient to classify the variant as Likely Pathogenic or Pathogenic. The variant remains a Variant of Uncertain Significance.

Met · 1

PM2 ModerateNM_198253.2:c.899G>A is absent from population databases. In gnomAD v4.1, the variant has 0 alleles across 1,571,010 total alleles (AF=0.00%), meeting the PM2 threshold for absence in population controls (AF < 0.1%). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: 0/1
  • 571
  • 010 alleles (AF=0.00%)
  • gnomAD-Canada v1.0: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 21 · evaluated, threshold not reached

PS1 No evidence that the same amino acid change (p.Gly300Asp) resulting from a different nucleotide substitution has been previously established as pathogenic. No alternate nucleotide change at codon 300 was identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • No alternate nucleotide substitution causing p.Gly300Asp is reported as pathogenic in ClinVar.
Still missing
  • No alternate nucleotide changes at codon 300 available for PS1 assessment.
Sources
clinvar ↗pm5_candidates
PS2 No de novo observation data for NM_198253.2:c.899G>A was identified. No family studies or de novo reports exist in the literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
  • No de novo data available.
Still missing
  • No parental testing or de novo reports for this variant.
PS3 No variant-specific functional data exists for NM_198253.2:c.899G>A (p.Gly300Asp). OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. No literature identified contains functional assay data for this variant or a systematically characterized range that includes position 300. Details ▾Hide ▴
Evidence considered
  • OncoKB classifies this variant as Unknown Oncogenic Effect
  • no functional publications identified.
Still missing
  • No functional studies (enzymatic activity
  • telomerase assay
  • protein stability) for p.Gly300Asp.
Sources
oncokb ↗
PS4 No case-control or cohort data demonstrating statistically significant enrichment of NM_198253.2:c.899G>A in affected individuals compared to controls. The sole ClinVar submission is a single clinical laboratory reporting Uncertain Significance without case-level phenotype data. Details ▾Hide ▴
Evidence considered
  • Single ClinVar submission as VUS
  • no published case series or case-control data.
Still missing
  • No case-control studies or phenotype-specific cohort data.
Sources
clinvar ↗
PM1 Position p.Gly300 is not located in a statistically significant mutational hotspot (cancerhotspots.org). While TERT contains well-characterized functional domains (TEN, TRBD, RT, CTE), no domain-level evidence specific to codon 300 was identified in the provided materials to support PM1 application. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org does not identify codon 300 as a significant hotspot.
Still missing
  • No residue-specific domain characterization for p.Gly300 in TERT.
PM5 No pathogenic missense variant at the same amino acid residue (p.Gly300) was identified in ClinVar. The PM5 candidate search returned no same-residue comparator variants. A different missense change at codon 300 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • No pathogenic missense variants at codon 300 identified in ClinVar.
Still missing
  • No known pathogenic comparator at p.Gly300.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation for NM_198253.2:c.899G>A was identified in ClinVar submissions or published literature. PM6 (assumed de novo without confirmed parentage) cannot be applied. Details ▾Hide ▴
Evidence considered
  • No de novo data available.
Still missing
  • No de novo or assumed de novo reports.
PP1 No co-segregation data is available for NM_198253.2:c.899G>A. No family studies or segregation analyses have been reported. Details ▾Hide ▴
Evidence considered
  • No co-segregation data available.
Still missing
  • No family studies or segregation data.
PP3 In silico predictors do not provide multiple lines of supporting evidence for pathogenicity. REVEL score is 0.283 (low/intermediate, not strongly pathogenic). BayesDel score is -0.187 (slightly in benign direction). SpliceAI predicts no splicing impact (max delta = 0.00). No consensus among predictors supports a damaging effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.283 (low/intermediate)
  • BayesDel: -0.187 (slightly benign)
  • SpliceAI: max delta 0.00 (no predicted splicing impact)
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or family history data is available for the proband carrying NM_198253.2:c.899G>A. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
  • No proband phenotype or family history data available.
Still missing
  • No proband clinical data provided.
PP5 ClinVar reports NM_198253.2:c.899G>A as Uncertain Significance (1 star, criteria provided by a single submitter). The PP5 threshold requires a 3-star expert panel classification as pathogenic. The single-submitter VUS classification does not meet criteria for PP5 at any strength level. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 2937435: Uncertain Significance
  • 1 submitter (Labcorp Genetics)
  • review status: criteria provided
  • single submitter. No expert panel review.
Sources
clinvar ↗
BA1 NM_198253.2:c.899G>A is absent from gnomAD (0/1,571,010 alleles). Does not exceed the BA1 threshold allele frequency of 5%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF=0.00%
  • well below 5% BA1 threshold.
Sources
gnomad_v4 ↗
BS1 NM_198253.2:c.899G>A is absent from gnomAD (0/1,571,010 alleles). Does not exceed the BS1 threshold allele frequency of 0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF=0.00%
  • well below 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
BS2 No homozygous observations of NM_198253.2:c.899G>A in gnomAD or other population databases. Cannot assess BS2 (observed in a healthy adult individual in a homozygous state for a fully penetrant dominant disorder) without homozygous carriers. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 0 homozygotes out of 1
  • 571
  • 010 alleles.
Sources
gnomad_v4 ↗
BS3 No well-established functional studies demonstrate a neutral effect for NM_198253.2:c.899G>A (p.Gly300Asp). No functional data is available for this variant. Details ▾Hide ▴
Evidence considered
  • OncoKB reports Unknown Oncogenic Effect
  • no functional studies identified.
Still missing
  • No functional studies demonstrating neutral effect.
Sources
oncokb ↗
BS4 No segregation data is available for NM_198253.2:c.899G>A. BS4 (lack of segregation in affected family members) cannot be assessed. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No segregation studies.
BP1 BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. TERT has both established pathogenic missense and truncating variants associated with telomere biology disorders (e.g., dyskeratosis congenita), so BP1 is not applicable. Details ▾Hide ▴
Evidence considered
  • TERT has known pathogenic missense variants in addition to truncating variants
  • BP1 criterion not satisfied.
Sources
pvs1_gene_context
BP2 No evidence that NM_198253.2:c.899G>A has been observed in trans with a known pathogenic variant in TERT for a recessive disorder. Telomere biology disorders associated with TERT are typically autosomal dominant, making BP2 generally not applicable. Details ▾Hide ▴
Evidence considered
  • TERT-related telomere biology disorders are primarily autosomal dominant
  • BP2 not applicable.
Sources
pvs1_gene_context
BP4 In silico predictors do not provide multiple lines of evidence suggesting no impact. REVEL score is 0.283 (intermediate, not strongly benign). BayesDel score is -0.187 (mildly in benign direction but does not reach a strong consensus). SpliceAI predicts no splicing impact. The evidence is insufficient for a BP4 designation which requires multiple lines of computational evidence suggesting no impact on the gene or gene product. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.283 (intermediate)
  • BayesDel: -0.187 (mildly benign but not consensus)
  • SpliceAI: max delta 0.00
Sources
revelbayesdelspliceai ↗
BP5 No evidence that NM_198253.2:c.899G>A has been observed in a case with an alternate molecular basis for disease. BP5 requires a variant to be found in a patient with an established alternative genetic cause of disease. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis data available.
Still missing
  • No proband data indicating alternative molecular diagnosis.
BP6 ClinVar reports NM_198253.2:c.899G>A as Uncertain Significance, not benign. The ClinVar entry has 1-star review status (criteria provided, single submitter); the 3-star expert panel threshold required for BP6 at supporting strength is not met. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 2937435: Uncertain Significance
  • 1 submitter. Does not meet 3-star expert panel threshold for BP6.
Sources
clinvar ↗

Not assessed · 1 · no assessment recorded

PP2 PP2 requires demonstration that the gene has a low rate of benign missense variation and that missense variants are a common mechanism of disease. Insufficient constraint data (HCI prior not available; no missense Z-score or regional constraint metrics) to assess PP2 for TERT. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for TERT
  • insufficient constraint metrics for PP2 assessment.
Still missing
  • No missense constraint metrics (Z-score
  • regional missense constraint) available for TERT.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_198253.2:c.899G>A is a missense variant (p.Gly300Asp), not a null variant (nonsense, frameshift, or canonical splice site). The generic PVS1 framework (PMC6185798) is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
  • Missense substitution does not qualify for PVS1 null-variant assessment.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP3 N/ANM_198253.2:c.899G>A is a single-nucleotide missense substitution, not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP3 applies only to in-frame indels in repetitive regions.
BP7 N/ANM_198253.2:c.899G>A is a missense variant (p.Gly300Asp), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 applies only to synonymous variants.
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion (PMID:25741868). No TERT-specific VCEP/CSPEC framework exists to provide a gene-specific definition for this code. Cannot adjudicate without a criterion definition. Details ▾Hide ▴
Evidence considered
  • No standard or VCEP definition available for PS5.

Identifiers

Gene
TERT
Transcript
NM_198253.2
Coding (HGVS c.)
NM_198253.2:c.899G>A
Protein (HGVS p.)
NP_937983.2:p.(Gly300Asp)
GRCh38
chr5:1293987 C>T
GRCh37
chr5:1294102 C>T
ClinVar
2937435

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 / 1,571,010 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 / 1,571,010 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%, 0/1571010 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73820 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.030
Pangolin splice gain
0.070

Other predictors

REVEL
0.283
BayesDel
-0.187

How the predictions were used

PP3 In silico predictors do not provide multiple lines of supporting evidence for pathogenicity. REVEL score is 0.283 (low/intermediate, not strongly pathogenic). BayesDel score is -0.187 (slightly in benign direction). SpliceAI predicts no splicing impact (max delta = 0.00). No consensus among predictors supports a damaging effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.283 (low/intermediate)
  • BayesDel: -0.187 (slightly benign)
  • SpliceAI: max delta 0.00 (no predicted splicing impact)
Sources
revelbayesdelspliceai ↗
BP4 In silico predictors do not provide multiple lines of evidence suggesting no impact. REVEL score is 0.283 (intermediate, not strongly benign). BayesDel score is -0.187 (mildly in benign direction but does not reach a strong consensus). SpliceAI predicts no splicing impact. The evidence is insufficient for a BP4 designation which requires multiple lines of computational evidence suggesting no impact on the gene or gene product. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.283 (intermediate)
  • BayesDel: -0.187 (mildly benign but not consensus)
  • SpliceAI: max delta 0.00
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_198253.2:c.899G>A is a missense variant (p.Gly300Asp), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 applies only to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.283. BayesDel score = -0.187223.

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. Provides general clinical and genetic overview of TERT-related disorders, including inheritance patterns and management. NM_198253.2:c.899G>A was not identified as a specifically discussed variant.
    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 / 1,571,010 recorded alleles 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

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1571010 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73820 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 = 2937435)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.283. BayesDel score = -0.187223.

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.