About TERT
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TERT c.835G>A, p.(Ala279Thr)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone
Population frequency is above the benign stand-alone threshold. This variant is present at 2.314% in gnomAD v2.1 and 2.712% in gnomAD v4.1, both above the 1% BA1 threshold.
BS1Strong
BS1 · strong
Population frequency is greater than expected for a pathogenic TERT variant. The allele frequency is 2.314% in gnomAD v2.1 and 2.712% in gnomAD v4.1, both above the 0.3% BS1 threshold.
BP4Supporting
BP4 · supporting
Multiple computational predictors support no damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.162, and BayesDel is -0.293678, which together support BP4.
Recorded classification: Benign
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP4 supporting benign; combination = 1 stand-alone benign, which maps to Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
43,173 / 1,592,140 alleles
gnomAD v4.1: 43,173 / 1,592,140 alleles. Recorded AF 0.0271163. Recorded homozygote count 703.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.0231414; MAF= 2.31414%, 5568/240608 alleles, homozygotes = 100) and has highest observed frequency in the European (Finnish) population (AF= 0.0588917; MAF= 5.88917%, 1118/18984 alleles, homozygotes = 30); grpmax FAF= 0.0337522.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 6 not met · 14 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The TERT c.835G>A (p.Ala279Thr, p.A279T) variant has been reported in ClinVar as benign by 18 clinical laboratories.
This variant is common in population databases, with a total allele frequency of 2.314% in gnomAD v2.1 and 2.712% in gnomAD v4.1; the highest observed population frequency is 5.889% in Finnish individuals in v2.1 and 5.675% in Finnish individuals in v4.1.
In silico results do not support a damaging effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.162, and BayesDel is -0.293678.
No criteria match.
Met · 3
BA1 Stand alonePopulation frequency is above the benign stand-alone threshold. This variant is present at 2.314% in gnomAD v2.1 and 2.712% in gnomAD v4.1, both above the 1% BA1 threshold. Details ▾Hide ▴
BS1 StrongPopulation frequency is greater than expected for a pathogenic TERT variant. The allele frequency is 2.314% in gnomAD v2.1 and 2.712% in gnomAD v4.1, both above the 0.3% BS1 threshold. Details ▾Hide ▴
BP4 SupportingMultiple computational predictors support no damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.162, and BayesDel is -0.293678, which together support BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- REVEL 0.162
- BayesDel -0.293678
Sources
Not met · 6 · evaluated, threshold not reached
PS4 Available evidence does not show enrichment of this variant in affected individuals compared with controls. This variant is common in population databases, with gnomAD total allele frequencies of 2.314% in v2.1 and 2.712% in v4.1, which argues against PS4. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF 0.0231414
- gnomAD v4.1 AF 0.0271163
- No case-control enrichment data identified
Sources
PM1 This variant has not been shown to lie in a well-established mutational hotspot or critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at residue A279. Details ▾Hide ▴
Evidence considered
- No hotspot row found for TERT A279
Still missing
- No curated domain-specific missense constraint evidence was identified for Ala279.
Sources
PM2 This variant is not absent or rare in population databases. Its allele frequency is 2.314% in gnomAD v2.1 and 2.712% in gnomAD v4.1, which is far above the usual PM2 rarity threshold of 0.1%. Details ▾Hide ▴
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.162, and BayesDel is -0.293678, which together do not support PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- REVEL 0.162
- BayesDel -0.293678
Sources
BS2 Although this variant is observed in many population samples, including homozygotes in gnomAD, the available data do not establish that these are well-phenotyped unaffected adults for a fully penetrant TERT-related disorder. BS2 was therefore not applied. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 homozygotes 100
- gnomAD v4.1 homozygotes 703
Still missing
- Population records do not provide phenotype confirmation for unaffected carriers.
Sources
BP1 This is a missense variant, but the available evidence does not show that missense variation in TERT is uniformly less likely to be pathogenic than truncating variation, so BP1 was not met. Details ▾Hide ▴
Evidence considered
- TERT has an established loss-of-function mechanism
- but missense pathogenicity was not excluded
Still missing
- No gene-specific rule supporting BP1 was identified.
Sources
pvs1_gene_context
Not assessed · 14 · no assessment recorded
PS1 No evidence was identified showing that another nucleotide change creates the same amino acid substitution with an established pathogenic classification, so PS1 was not assessed. Details ▾Hide ▴
Still missing
- No verified same-amino-acid pathogenic comparator was identified.
PS2 No confirmed de novo occurrence with parental testing was identified for this variant, so PS2 was not assessed. Details ▾Hide ▴
Evidence considered
- ClinVar record reviewed without confirmed de novo evidence
Still missing
- Parental testing and phenotype-specific de novo data were not identified.
Sources
PS3 No well-established functional study for this exact variant was identified that demonstrates a damaging effect, so PS3 was not assessed. Details ▾Hide ▴
Evidence considered
- No variant-specific reviewed functional evidence identified in retrieved sources
Still missing
- No validated variant-specific functional assay data were identified.
Sources
PM3 No evidence was identified regarding occurrence of this variant in trans with a pathogenic variant in a recessive disease context, so PM3 was not assessed. Details ▾Hide ▴
Still missing
- Phase and recessive case-level data were not identified.
PM6 No probable de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not assessed. Details ▾Hide ▴
Evidence considered
- ClinVar record reviewed without probable de novo evidence
Still missing
- No reported probable de novo observation was identified.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Evidence considered
- No segregation evidence identified in reviewed materials
Still missing
- No informative meioses or family segregation reports were identified.
Sources
PP2 No gene-specific evidence was identified showing that TERT is a gene in which pathogenic missense variation is the predominant disease mechanism with a low rate of benign missense variation, so PP2 was not assessed. Details ▾Hide ▴
Still missing
- No validated gene-level missense mechanism framework was identified.
PP4 No phenotype data specific enough to show that the individual's presentation is highly specific for a TERT-related disorder were identified, so PP4 was not assessed. Details ▾Hide ▴
Still missing
- No case-specific phenotype information was provided.
PP5 PP5 was not used because no qualifying reputable-source pathogenic assertion independent of the underlying evidence review was identified. Details ▾Hide ▴
BS3 No well-established functional study for this exact variant was identified showing normal or near-normal function, so BS3 was not assessed. Details ▾Hide ▴
Evidence considered
- No variant-specific reviewed functional evidence identified in retrieved sources
Still missing
- No validated benign functional assay data were identified for this variant.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Evidence considered
- No non-segregation evidence identified in reviewed materials
Still missing
- No family study showing lack of segregation was identified.
Sources
BP2 No phase information or co-occurrence data with another pathogenic variant were identified, so BP2 was not assessed. Details ▾Hide ▴
Still missing
- No co-occurrence or phasing data were identified.
BP5 No evidence was identified for an alternate molecular cause that fully explains the phenotype, so BP5 was not assessed. Details ▾Hide ▴
Still missing
- No alternate-cause evaluation was available.
BP6 BP6 was not used because no qualifying reputable-source benign assertion independent of the underlying evidence review was established for this pass. Details ▾Hide ▴
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, p.(Ala279Thr), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Although loss of function is an established disease mechanism for TERT, the available generic PVS1 assessment does not support applying PVS1 to this variant. Details ▾Hide ▴
Evidence considered
- Missense variant p.(Ala279Thr)/p.(A279T)
- Generic PVS1 scaffold states this variant is outside default null-variant buckets
Sources
PM4 N/AThis variant is a missense substitution and does not cause a protein length change from an in-frame insertion/deletion or stop-loss event, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense substitution p.(Ala279Thr)
PM5 N/AThe available review could not confirm that classic same-residue PM5 logic should be applied for this gene/framework, and no validated same-residue pathogenic comparator was established. PM5 was therefore not applied. Details ▾Hide ▴
Evidence considered
- PM5 candidate review marked classic PM5 semantics as unconfirmed
Still missing
- No qualifying same-residue pathogenic comparator was confirmed.
Sources
pm5_candidates
BP3 N/AThis criterion applies to in-frame insertions/deletions in repetitive regions and is not applicable to this missense substitution. Details ▾Hide ▴
Evidence considered
- Missense substitution p.(Ala279Thr)
BP7 N/AThis criterion applies to synonymous or certain intronic variants without predicted splice impact and is not applicable to this missense substitution. Details ▾Hide ▴
Evidence considered
- Missense substitution p.(Ala279Thr)
Identifiers
- Gene
- TERT
- Transcript
- NM_198253.2
- Coding (HGVS c.)
- NM_198253.2:c.835G>A
- Protein (HGVS p.)
- NP_937983.2:p.(Ala279Thr)
- GRCh38
- chr5:1294051 C>T
- GRCh37
- chr5:1294166 C>T
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TERT
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
43,173 / 1,592,140 alleles
AF 0.0271 · 703 homozygotes · FAF 0.0298
gnomAD v2.1
5,568 / 240,608 alleles
AF 0.0231 · 100 homozygotes · FAF 0.0338
By genetic ancestry
gnomAD v4.1
AF 0.027 · 43173 / 1,592,140 alleles · 703 hom · FAF 0.03
| European (Finnish)3317 / 58,452 | 0.05799 hom |
| European (non-Finnish)35244 / 1,171,484 | 0.03536 hom |
| Ashkenazi Jewish869 / 29,254 | 0.0316 hom |
| Remaining individuals1487 / 61,652 | 0.02421 hom |
| South Asian1223 / 88,730 | 0.01424 hom |
| Admixed American623 / 57,978 | 0.0115 hom |
| Middle Eastern58 / 6,036 | 0.00961 hom |
| African/African American345 / 74,420 | 0.00461 hom |
| Amish4 / 912 | 0.0044 |
| East Asian3 / 43,222 | 6.9e-05 |
gnomAD v2.1
AF 0.023 · 5568 / 240,608 alleles · 100 hom · FAF 0.034
| European (Finnish)1118 / 18,984 | 0.05930 hom |
| European (non-Finnish)3208 / 106,710 | 0.0346 hom |
| Ashkenazi Jewish286 / 9,610 | 0.035 hom |
| Remaining individuals169 / 6,458 | 0.0268 hom |
| South Asian348 / 27,822 | 0.01310 hom |
| Admixed American337 / 32,630 | 0.011 hom |
| African/African American99 / 21,242 | 0.0047 |
| East Asian3 / 17,152 | 0.00017 |
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.0271163; MAF= 2.71163%, 43173/1592140 alleles, homozygotes = 703) and has highest observed frequency in the European (Finnish) population (AF= 0.0567474; MAF= 5.67474%, 3317/58452 alleles, homozygotes = 99); grpmax FAF= 0.0298216.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.0231414; MAF= 2.31414%, 5568/240608 alleles, homozygotes = 100) and has highest observed frequency in the European (Finnish) population (AF= 0.0588917; MAF= 5.88917%, 1118/18984 alleles, homozygotes = 30); grpmax FAF= 0.0337522.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingMultiple computational predictors support no damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.162, and BayesDel is -0.293678, which together support BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- REVEL 0.162
- BayesDel -0.293678
Sources
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.162, and BayesDel is -0.293678, which together do not support PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- REVEL 0.162
- BayesDel -0.293678
Sources
BP7 N/AThis criterion applies to synonymous or certain intronic variants without predicted splice impact and is not applicable to this missense substitution. Details ▾Hide ▴
Evidence considered
- Missense substitution p.(Ala279Thr)
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.162. BayesDel score = -0.293678.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
43,173 / 1,592,140 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/39125/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-1294166-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-1294051-C-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_198253.2%3Ac.835G…
- OncoKB ↗www.oncokb.org/gene/TERT/A279T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=111750053
- Cancer hotspots ↗www.cancerhotspots.org/
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= 0.0271163; MAF= 2.71163%, 43173/1592140 alleles, homozygotes = 703) and has highest observed frequency in the European (Finnish) population (AF= 0.0567474; MAF= 5.67474%, 3317/58452 alleles, homozygotes = 99); grpmax FAF= 0.0298216.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.0231414; MAF= 2.31414%, 5568/240608 alleles, homozygotes = 100) and has highest observed frequency in the European (Finnish) population (AF= 0.0588917; MAF= 5.88917%, 1118/18984 alleles, homozygotes = 30); grpmax FAF= 0.0337522.
ClinVar
This variant has been reported in ClinVar as Benign (18 clinical laboratories). (ClinVarID = 39125)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.162. BayesDel score = -0.293678.
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; COSV57209966, n = 11 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.