About TERT
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TERT c.833C>T, p.(Pro278Leu)
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.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is extremely rare in population databases: gnomAD v2.1 allele frequency is 9.83e-6 (0.00098%, 2/203,400 alleles), v4.1 is 3.77e-6 (0.00038%, 6/1,590,960 alleles), and absent from gnomAD-Canada. All frequencies are well below the 0.1% PM2 threshold for non-VCEP frameworks.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence support no impact on the gene product: REVEL score 0.137 (below pathogenic threshold), BayesDel score -0.244664 (predicts benign effect), and SpliceAI max delta 0.02 (no predicted splicing alteration).
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.
gnomAD v4.1
gnomAD v2.1
Population frequency
6 / 1,590,960 alleles
gnomAD v4.1: 6 / 1,590,960 alleles. Recorded AF 3.77131e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 9.83284e-06; MAF= 0.00098%, 2/203400 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.26127e-05; MAF= 0.00226%, 2/88446 alleles, homozygotes = 0); grpmax FAF= 3.75e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Likely benign. 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
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.
Met
Not met
Not assessed
Not applicable
NM_198253.2:c.833C>T (p.Pro278Leu) in TERT is a rare missense variant with extremely low population frequency (gnomAD v2.1 AF=9.83e-6, v4.1 AF=3.77e-6), meeting PM2 at supporting strength.
Multiple in silico predictors (REVEL 0.137, BayesDel -0.245, SpliceAI max delta 0.02) consistently suggest no damaging effect on the gene product, meeting BP4 at supporting benign strength.
This variant has been reported in ClinVar as Likely benign by a single clinical laboratory (Labcorp Genetics/Invitae, 1-star review status, SCV000824613). The classification and review status do not meet thresholds for PP5 or BP6 application under the 3-star expert panel requirement.
No variant-specific functional data, de novo observations, segregation data, case-control studies, or domain-level hotspot evidence were identified. OncoKB reports Unknown Oncogenic Effect. PM1 is not met as Pro278 is not in a statistically significant mutational hotspot.
PVS1 is not applicable (missense variant outside null-variant buckets). PS1, PM5, BP7, BP3, PM3, and PM4 are not applicable due to variant type or absence of required evidence patterns.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is in equipoise. The final classification under generic ACMG/AMP 2015 rules (Richards et al., PMID:25741868) is Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is extremely rare in population databases: gnomAD v2.1 allele frequency is 9.83e-6 (0.00098%, 2/203,400 alleles), v4.1 is 3.77e-6 (0.00038%, 6/1,590,960 alleles), and absent from gnomAD-Canada. All frequencies are well below the 0.1% PM2 threshold for non-VCEP frameworks. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=9.83e-6 (2/203
- 400)
- highest subpopulation NFE AF=2.26e-5 (0.00226%)
- gnomAD v4.1: AF=3.77e-6 (6/1
- 590
- 960)
- highest subpopulation 'remaining' AF=3.25e-5 (0.00325%)
- gnomAD-Canada: absent (0 alleles)
Sources
BP4 SupportingMultiple lines of computational evidence support no impact on the gene product: REVEL score 0.137 (below pathogenic threshold), BayesDel score -0.244664 (predicts benign effect), and SpliceAI max delta 0.02 (no predicted splicing alteration). Details ▾Hide ▴
Evidence considered
- REVEL: 0.137 (not predicted damaging)
- BayesDel: -0.244664 (predicted benign)
- SpliceAI: max delta 0.02
- no splice impact predicted
Sources
Not met · 20 · evaluated, threshold not reached
PS1 No evidence of a different nucleotide change at codon 278 producing the same Pro278Leu missense change with established pathogenicity; PS1 requires a proven pathogenic same-amino-acid change via a different nucleotide variant. Details ▾Hide ▴
Still missing
- No alternate nucleotide variant at codon 278 reported in ClinVar or literature
PS2 No de novo occurrence data available for this variant in any publication or database. Details ▾Hide ▴
Still missing
- No parental testing or de novo reports identified
PS3 No variant-specific functional studies identified. OncoKB reports Unknown Oncogenic Effect. In silico predictions (REVEL 0.137, BayesDel -0.245) do not support a damaging effect and do not constitute functional evidence for PS3. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no curated functional data for this variant
- REVEL score 0.137 does not predict damaging effect
- BayesDel score -0.244664 predicts benign effect
Still missing
- No experimental functional data available for this variant or a systematically characterized range covering Pro278
Sources
PS4 No case-control data or statistically significant enrichment of this variant in affected individuals versus controls available. The variant is extremely rare in gnomAD but no disease cohort comparison exists. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 2/203
- 400 alleles
- v4.1: 6/1
- 590
- 960 alleles
- no case-control comparison available
Still missing
- No case-control or cohort enrichment data
Sources
PM1 Pro278 is not located within a statistically significant mutational hotspot (cancerhotspots.org negative). No domain-level evidence was retrieved establishing that position 278 resides in a critical, well-characterized functional domain of TERT without benign variation. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant
- exact variant not listed
- OncoKB: no domain-level functional annotation specific to Pro278
Still missing
- No established critical functional domain annotation for Pro278 in TERT
Sources
PM6 No de novo occurrence reported for this variant in any publication or database. Details ▾Hide ▴
Still missing
- No de novo reports identified
PP1 No segregation data available for this variant in affected families. Details ▾Hide ▴
Still missing
- No family segregation studies identified
PP2 Insufficient data to establish that TERT has a low rate of benign missense variation. No gnomAD Z-score or missense constraint metrics were retrieved, which are required for PP2 application. Details ▾Hide ▴
Still missing
- No gnomAD gene constraint data (Z-score
- missense OE ratio) available to assess low benign missense variation rate
PP3 Multiple in silico predictors do not support a damaging effect: REVEL score is 0.137 (well below ~0.5 pathogenic threshold), BayesDel is -0.245 (negative score consistent with benign effect), and SpliceAI predicts no splicing impact (max delta 0.02). These tools collectively suggest the variant is tolerated. Details ▾Hide ▴
Evidence considered
- REVEL: 0.137 (not predicted damaging)
- BayesDel: -0.244664 (predicted benign)
- SpliceAI: max delta 0.02 (no splice impact)
Sources
PP4 No patient phenotype or family history data specific to this variant are available to assess whether the clinical presentation matches TERT-related telomere biology disorders. Details ▾Hide ▴
Still missing
- No clinical phenotype data for carriers of this variant
PP5 ClinVar classification is Likely benign (not pathogenic) from a single submitter (Labcorp Genetics/Invitae). PP5 requires a reputable source reporting the variant as pathogenic, and supporting-level application requires 3-star expert panel review status. Neither condition is met: the classification is benign-directed and the review status is 1-star (criteria provided, single submitter). Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 574198: Likely benign
- 1-star (criteria provided
- single submitter)
- 1 clinical laboratory (Labcorp Genetics)
Sources
BA1 gnomAD allele frequencies (v2.1: 0.00098%, v4.1: 0.00038%) are well below the 1% BA1 threshold for non-VCEP frameworks. Highest subpopulation frequency is 0.00325% (v4.1 remaining individuals). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=9.83e-6 (0.00098%)
- gnomAD v4.1 AF=3.77e-6 (0.00038%)
Sources
BS1 gnomAD allele frequencies (v2.1: 0.00098%, v4.1: 0.00038%) are well below the 0.3% BS1 threshold. Highest subpopulation frequency is 0.00325% (v4.1 remaining individuals). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=9.83e-6 (0.00098%)
- gnomAD v4.1 AF=3.77e-6 (0.00038%)
Sources
BS2 No homozygous observations in gnomAD and no evidence that this variant has been observed in healthy adults in the context of a fully penetrant dominant disorder. Zero homozygotes across all population databases. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 homozygotes
- gnomAD v4.1: 0 homozygotes
Still missing
- No healthy adult carrier data available
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this variant. In silico predictions alone (REVEL 0.137, BayesDel -0.245) do not constitute BS3-level functional evidence. Details ▾Hide ▴
Evidence considered
- REVEL 0.137 and BayesDel -0.244664 suggest benign effect but are not well-established functional assays
Still missing
- No experimental functional studies (e.g.
- telomerase activity assay
- telomere length measurement) performed for this variant
Sources
revelbayesdel
BS4 No segregation data demonstrating lack of cosegregation with disease in affected families. Details ▾Hide ▴
Still missing
- No family segregation data available
BP1 TERT-related disease is known to be caused by both missense and truncating variants. BP1 applies only to genes where primarily truncating variants cause disease, which is not the case for TERT. Details ▾Hide ▴
Evidence considered
- TERT has pathogenic missense and truncating variants associated with telomere biology disorders (dyskeratosis congenita
- MDS)
BP2 No observation of this variant in trans with a known pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- No phased genotype data available
BP5 No observation of this variant in a case where an alternative molecular basis for disease has been identified. Details ▾Hide ▴
Still missing
- No co-occurring pathogenic variant data
BP6 ClinVar review status is 1-star (criteria provided, single submitter). BP6 supporting-level application requires a 3-star expert panel classification as benign or likely benign. The single-submitter Likely benign classification from Labcorp Genetics does not meet this threshold. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 574198: Likely benign
- 1-star (criteria provided
- single submitter)
- Labcorp Genetics/Invitae
Sources
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (c.833C>T, p.Pro278Leu) does not fall into null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Generic PVS1 framework is not applicable. Details ▾Hide ▴
Evidence considered
- Variant bucket classified as 'other' (missense substitution)
- apply_generic_pvs1_framework=false per ClinGen SVI PVS1 recommendations (PMC6185798)
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ARecessive disorder criterion; TERT-related disorders exhibit dominant and recessive inheritance patterns but no in trans observations are available for this variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ANon-repeat in-frame indel or stop-loss criterion; this is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue comparator variants identified. Automated PM5 candidate harvesting found no ClinVar variants at codon 278 with established pathogenicity. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates found
- PM5 mode=unknown
- not eligible for classic same-residue search
Still missing
- No pathogenic missense variants at codon 278 in ClinVar or literature
Sources
pm5_candidates
BP3 N/AIn-frame indel criterion; this is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ASynonymous/non-coding variant criterion. This is a missense variant (c.833C>T, p.Pro278Leu) and BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a defined criterion in the ACMG/AMP 2015 framework (Richards et al., PMID:25741868). No framework-specific PS5 definition was retrieved for this case. Details ▾Hide ▴
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- TERT
- Transcript
- NM_198253.2
- Coding (HGVS c.)
- NM_198253.2:c.833C>T
- Protein (HGVS p.)
- NP_937983.2:p.(Pro278Leu)
- GRCh38
- chr5:1294053 G>A
- GRCh37
- chr5:1294168 G>A
- ClinVar
- 574198, 1404633
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
6 / 1,590,960 alleles
AF 3.77e-06 · 0 homozygotes · FAF 8e-07
gnomAD v2.1
2 / 203,400 alleles
AF 9.83e-06 · 0 homozygotes · FAF 3.75e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.8e-06 · 6 / 1,590,960 alleles · 0 hom · FAF 8e-07
| Remaining individuals2 / 61,602 | 3.2e-05 |
| European (non-Finnish)4 / 1,170,984 | 3.4e-06 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 9.8e-06 · 2 / 203,400 alleles · 0 hom · FAF 3.8e-06
| European (non-Finnish)2 / 88,446 | 2.3e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.77131e-06; MAF= 0.00038%, 6/1590960 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.24665e-05; MAF= 0.00325%, 2/61602 alleles, homozygotes = 0); grpmax FAF= 8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 9.83284e-06; MAF= 0.00098%, 2/203400 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.26127e-05; MAF= 0.00226%, 2/88446 alleles, homozygotes = 0); grpmax FAF= 3.75e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.137
- BayesDel
- -0.245
How the predictions were used
BP4 SupportingMultiple lines of computational evidence support no impact on the gene product: REVEL score 0.137 (below pathogenic threshold), BayesDel score -0.244664 (predicts benign effect), and SpliceAI max delta 0.02 (no predicted splicing alteration). Details ▾Hide ▴
Evidence considered
- REVEL: 0.137 (not predicted damaging)
- BayesDel: -0.244664 (predicted benign)
- SpliceAI: max delta 0.02
- no splice impact predicted
Sources
PP3 Multiple in silico predictors do not support a damaging effect: REVEL score is 0.137 (well below ~0.5 pathogenic threshold), BayesDel is -0.245 (negative score consistent with benign effect), and SpliceAI predicts no splicing impact (max delta 0.02). These tools collectively suggest the variant is tolerated. Details ▾Hide ▴
Evidence considered
- REVEL: 0.137 (not predicted damaging)
- BayesDel: -0.244664 (predicted benign)
- SpliceAI: max delta 0.02 (no splice impact)
Sources
BP7 N/ASynonymous/non-coding variant criterion. This is a missense variant (c.833C>T, p.Pro278Leu) and BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.137. BayesDel score = -0.244664.
2 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
-
PMID 20301779 ↗Dyskeratosis Congenita and Related Telomere Biology Disorders.Adam MP et al. · 1993GeneReviews chapter on Dyskeratosis Congenita and Related Telomere Biology Disorders. This is a broad clinical overview discussing TERT in the context of telomere biology disorders at the gene level. NM_198253.2:c.833C>T was not identified in the available abstract.Does not name this variant
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. This is a methodology paper describing a variant classification framework refinement. NM_198253.2:c.833C>T is not discussed in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
6 / 1,590,960 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
1 Likely benign
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/574198/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-1294168-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-1294053-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-1294053-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_198253.2%3Ac.833C…
- OncoKB ↗www.oncokb.org/gene/TERT/P278L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TERT+c.833C%3ET
- 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= 3.77131e-06; MAF= 0.00038%, 6/1590960 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.24665e-05; MAF= 0.00325%, 2/61602 alleles, homozygotes = 0); grpmax FAF= 8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 9.83284e-06; MAF= 0.00098%, 2/203400 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.26127e-05; MAF= 0.00226%, 2/88446 alleles, homozygotes = 0); grpmax FAF= 3.75e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 574198)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.137. BayesDel score = -0.244664.
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.