About TERT
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TERT c.2775C>T, p.(His925=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely 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
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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: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BP6Supporting
BP6 · supporting
ClinVar reports this variant as Likely benign by 9 clinical laboratories and Benign by 5 clinical laboratories (Variation ID 242230). Fourteen independent clinical laboratory submissions converge on a benign interpretation. Review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel, but the volume and consistency of benign classifications from multiple clinical testing laboratories supports a benign interpretation under generic ACMG.
BP7Supporting
BP7 · supporting
Synonymous variant (p.His925=) with SpliceAI predicting no splice impact (max delta score = 0.00). The high population frequency (up to 2% in Ashkenazi Jewish, with 12 homozygotes in gnomAD v4.1) suggests the nucleotide is not highly conserved. A silent variant with no predicted splicing effect and no conservation constraint meets BP7.
Recorded classification: Likely 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: BP6 supporting benign, BP7 supporting benign; combination = 2 supporting benign, which maps to Likely 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
1,208 / 1,613,858 alleles
gnomAD v4.1: 1,208 / 1,613,858 alleles. Recorded AF 0.000748517. Recorded homozygote count 12.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00105174; MAF= 0.10517%, 295/280488 alleles, homozygotes = 5) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0198183; MAF= 1.98183%, 205/10344 alleles, homozygotes = 5); grpmax FAF= 0.00036814.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0018458197611292075, 34/18420 alleles, homozygotes = 0).
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
14 reported laboratory submissions
9 Likely benign · 5 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
4 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57220253, n = 4 times).
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.
26 criteria with recorded statuses: 2 met · 19 not met · 0 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
NM_198253.2:c.2775C>T is a synonymous variant (p.His925=) in exon 11 of TERT. SpliceAI predicts no splicing impact (delta score = 0.00).
This variant is present in gnomAD v4.1 at a global allele frequency of 0.075% (1208/1,613,858 alleles) with 12 homozygotes observed, and is common in the Ashkenazi Jewish subpopulation (~2%).
ClinVar classifies this variant as Likely benign by 9 clinical laboratories and Benign by 5 clinical laboratories (Variation ID 242230), representing a strong consensus of benign interpretation across 14 independent clinical testing laboratories.
No publication was found that mentions this specific variant (NM_198253.2:c.2775C>T). The TERT functional study by Yamaguchi et al. (PMID:15814878) examined only nonsynonymous mutations at codons 202, 412, 694, 772, and 1090. The ACMG/AMP guidelines paper (PMID:25741868) does not discuss individual variants. GeneReviews and PDQ summaries (PMIDs:20301408, 20301779, 26389258, 26389333) provide general gene-level overviews without variant-specific data.
Two supporting benign criteria are met: BP6 (ClinVar consensus of benign classification by multiple clinical laboratories) and BP7 (synonymous variant with no predicted splice impact, and the nucleotide is not conserved as evidenced by high population frequency with multiple homozygotes). Under ACMG/AMP 2015 combination rules, ≥2 supporting benign criteria yields a classification of Likely benign.
No criteria match.
Met · 2
BP6 SupportingClinVar reports this variant as Likely benign by 9 clinical laboratories and Benign by 5 clinical laboratories (Variation ID 242230). Fourteen independent clinical laboratory submissions converge on a benign interpretation. Review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel, but the volume and consistency of benign classifications from multiple clinical testing laboratories supports a benign interpretation under generic ACMG. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 242230: Likely benign (9 labs)
- Benign (5 labs)
- 14 usable clinical laboratory submissions
- all converging on benign
Sources
BP7 SupportingSynonymous variant (p.His925=) with SpliceAI predicting no splice impact (max delta score = 0.00). The high population frequency (up to 2% in Ashkenazi Jewish, with 12 homozygotes in gnomAD v4.1) suggests the nucleotide is not highly conserved. A silent variant with no predicted splicing effect and no conservation constraint meets BP7. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no splice impact predicted
- p.His925= — synonymous
- no amino acid change
- gnomAD: 12 homozygotes observed
- Ashkenazi Jewish AF ~2% — consistent with non-conserved nucleotide
Sources
Not met · 19 · evaluated, threshold not reached
PS2 No de novo data available for this variant. Details ▾Hide ▴
Still missing
- No de novo testing or family studies available
PS3 No functional data exists for this synonymous variant. The published TERT functional studies (PMID:15814878) examined nonsynonymous mutations at codons 202, 412, 694, 772, and 1090, not residue 925. Details ▾Hide ▴
Evidence considered
- No functional studies of NM_198253.2:c.2775C>T in any publication
Still missing
- No variant-specific functional data
Sources
PS4 No case-control data or statistically significant enrichment of this variant in affected individuals versus controls. Details ▾Hide ▴
Still missing
- No case-control studies available
PM1 This synonymous variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org negative), and position 925 is not within a characterized critical functional domain that a synonymous change would disrupt. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant
- Synonymous change does not alter protein domain structure
PM2 Global allele frequency in gnomAD v4.1 is 0.075% (1208/1,613,858 alleles), approaching the 0.1% PM2 threshold. The variant is common in the Ashkenazi Jewish subpopulation (~2%) with 12 homozygotes observed, which is inconsistent with a rare pathogenic variant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.105%
- 295/280488 alleles
- 5 homozygotes
- gnomAD v4.1: AF=0.075%
- 1208/1613858 alleles
- 12 homozygotes
- Ashkenazi Jewish subpopulation: AF=1.92-1.98%
Sources
PM6 No de novo observation reported for this variant. Details ▾Hide ▴
Still missing
- No de novo data available
PP1 No segregation data available for this variant. Details ▾Hide ▴
Still missing
- No cosegregation studies
PP3 SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL, BayesDel, and HCI Prior scores are unavailable for this synonymous variant. No in silico evidence supports a damaging effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- REVEL/BayesDel not applicable (missense-specific tools)
Sources
PP4 No patient phenotype or family history data available to assess specificity for a TERT-related disorder. Details ▾Hide ▴
Still missing
- No clinical phenotype data provided
PP5 ClinVar classifies this variant as Likely benign/Benign (Variation ID 242230), not pathogenic. No expert panel has reported it as pathogenic. The ClinVar review status is 'criteria provided, single submitter' (1-star), not the 3-star expert panel threshold. Details ▾Hide ▴
Evidence considered
- ClinVar: Likely benign (9 labs)
- Benign (5 labs)
- No expert panel review
- not 3-star
Sources
BA1 Global allele frequency in gnomAD is below 1% (v2.1: 0.105%, v4.1: 0.075%). The Ashkenazi Jewish subpopulation frequency of ~2% does not satisfy BA1 under global population conventions. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 global AF = 0.105%
- gnomAD v4.1 global AF = 0.075%
Sources
BS1 Global allele frequency in gnomAD is below 0.3% (v2.1: 0.105%, v4.1: 0.075%). Does not meet the >0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 global AF = 0.105%
- gnomAD v4.1 global AF = 0.075%
Sources
BS2 No specific observation of this variant in healthy adults documented with expected full-penetrance early-age phenotype absent. Details ▾Hide ▴
Still missing
- No clinical observation data with phenotype
BS3 No functional studies have been performed on this variant to demonstrate no damaging effect on protein function or splicing. Details ▾Hide ▴
Still missing
- No functional data for this variant
BS4 No segregation data available to demonstrate lack of cosegregation with disease. Details ▾Hide ▴
Still missing
- No segregation data
BP2 No evidence that this variant has been observed in trans with a pathogenic variant in a recessive disorder. Details ▾Hide ▴
Still missing
- No trans-phase data
BP4 Insufficient multiple lines of computational evidence. Only SpliceAI is available (delta=0.00); REVEL, BayesDel, and conservation scores are not applicable or unavailable for this synonymous variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- No additional in silico predictors available for synonymous variants
Still missing
- No conservation or evolutionary constraint data
Sources
BP5 No observation of this variant in a case where an alternate molecular basis for disease was identified. Details ▾Hide ▴
Still missing
- No alternate-molecular-basis data
PS5 No experimental evidence that this synonymous variant affects gene function through an established functional assay. Details ▾Hide ▴
Still missing
- No experimental functional assessment for this variant
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ASynonymous variant (p.His925=) produces no null effect on the protein; does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical splice site). Details ▾Hide ▴
Evidence considered
- NP_937983.2:p.(His925=) — no amino acid change
- Variant class: substitution (synonymous)
Sources
PS1 N/ASynonymous variant produces no amino acid change; there is no same-amino-acid-change comparator possible. Details ▾Hide ▴
Evidence considered
- p.His925= — synonymous
- no alternative amino acid
PM5 N/ASynonymous variant produces no amino acid change; unable to assess same-residue alternate missense comparator. Details ▾Hide ▴
Evidence considered
- p.His925= — synonymous
- no residue change
PP2 N/APP2 applies to missense variants in genes with low rate of benign missense variation. This is a synonymous variant. Details ▾Hide ▴
Evidence considered
- Synonymous variant — PP2 is a missense-specific criterion
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is a synonymous variant. Details ▾Hide ▴
Evidence considered
- Synonymous variant — BP1 is missense-specific
Identifiers
- Gene
- TERT
- Transcript
- NM_198253.2
- Coding (HGVS c.)
- NM_198253.2:c.2775C>T
- Protein (HGVS p.)
- NP_937983.2:p.(His925=)
- GRCh38
- chr5:1264472 G>A
- GRCh37
- chr5:1264587 G>A
- ClinVar
- 242230
- COSMIC
- COSV57220253
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
1,208 / 1,613,858 alleles
AF 0.000749 · 12 homozygotes · FAF 0.00427
gnomAD v2.1
295 / 280,488 alleles
AF 0.00105 · 5 homozygotes · FAF 0.000368
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00075 · 1208 / 1,613,858 alleles · 12 hom · FAF 0.0043
| Ashkenazi Jewish567 / 29,608 | 0.01910 hom |
| Middle Eastern35 / 6,062 | 0.0058 |
| Remaining individuals131 / 62,504 | 0.00211 hom |
| East Asian78 / 44,876 | 0.0017 |
| African/African American40 / 75,052 | 0.00053 |
| Admixed American20 / 60,032 | 0.00033 |
| European (non-Finnish)321 / 1,180,032 | 0.00027 |
| South Asian14 / 91,090 | 0.000151 hom |
| European (Finnish)2 / 63,690 | 3.1e-05 |
0 alternate alleles recorded in 1 other group: Amish.
gnomAD v2.1
AF 0.0011 · 295 / 280,488 alleles · 5 hom · FAF 0.00037
| Ashkenazi Jewish205 / 10,344 | 0.025 hom |
| Remaining individuals9 / 7,142 | 0.0013 |
| European (non-Finnish)56 / 128,346 | 0.00044 |
| East Asian8 / 19,530 | 0.00041 |
| Admixed American11 / 35,364 | 0.00031 |
| African/African American3 / 24,154 | 0.00012 |
| South Asian3 / 30,602 | 9.8e-05 |
0 alternate alleles recorded in 1 other group: European (Finnish).
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000748517; MAF= 0.07485%, 1208/1613858 alleles, homozygotes = 12) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0191502; MAF= 1.91502%, 567/29608 alleles, homozygotes = 10); grpmax FAF= 0.00426711.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00105174; MAF= 0.10517%, 295/280488 alleles, homozygotes = 5) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0198183; MAF= 1.98183%, 205/10344 alleles, homozygotes = 5); grpmax FAF= 0.00036814.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0018458197611292075, 34/18420 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingSynonymous variant (p.His925=) with SpliceAI predicting no splice impact (max delta score = 0.00). The high population frequency (up to 2% in Ashkenazi Jewish, with 12 homozygotes in gnomAD v4.1) suggests the nucleotide is not highly conserved. A silent variant with no predicted splicing effect and no conservation constraint meets BP7. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no splice impact predicted
- p.His925= — synonymous
- no amino acid change
- gnomAD: 12 homozygotes observed
- Ashkenazi Jewish AF ~2% — consistent with non-conserved nucleotide
Sources
PP3 SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL, BayesDel, and HCI Prior scores are unavailable for this synonymous variant. No in silico evidence supports a damaging effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- REVEL/BayesDel not applicable (missense-specific tools)
Sources
BP4 Insufficient multiple lines of computational evidence. Only SpliceAI is available (delta=0.00); REVEL, BayesDel, and conservation scores are not applicable or unavailable for this synonymous variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- No additional in silico predictors available for synonymous variants
Still missing
- No conservation or evolutionary constraint data
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
7 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
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PMID 15814878 ↗Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia.Yamaguchi H et al. · 2005Identified five heterozygous nonsynonymous TERT mutations (codons 202, 412, 694, 772, 1090) in 7 unrelated patients with aplastic anemia. Demonstrated that these mutations impair telomerase activity by haploinsufficiency. NM_198253.2:c.2775C>T (p.His925=) was not among the variants studied.Does not name this variant
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PMID 25741868 ↗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.Standards and guidelines for ACMG/AMP sequence variant interpretation. Does not discuss individual variants; provides the classification framework and criteria definitions used in this assessment.Does not name this variant
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PMID 20301408 ↗Pulmonary Fibrosis Predisposition Overview.GeneReviews overview of pulmonary fibrosis predisposition. Gene-level summary of TERT-associated disease; no variant-specific data for NM_198253.2:c.2775C>T.Does not name this variant
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PMID 20301779 ↗Dyskeratosis Congenita and Related Telomere Biology Disorders.Adam MP et al. · 1993GeneReviews overview of dyskeratosis congenita and telomere biology disorders. Gene-level description of TERT-related disease; no variant-specific data.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics risk assessment and counseling summary. General cancer genetics resource; no variant-specific data.Does not name this variant
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PMID 26389333 ↗Genetics of Skin Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ genetics of skin cancer summary. General cancer genetics resource; no variant-specific data.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc refinement of ACMG-AMP classification criteria. Methodology paper; does not discuss individual TERT variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1,208 / 1,613,858 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
9 Likely benign · 5 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/242230/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-1264587-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-1264472-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-1264472-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_198253.2%3Ac.2775…
- OncoKB ↗www.oncokb.org/gene/TERT/H925=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=127110191
- 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= 0.000748517; MAF= 0.07485%, 1208/1613858 alleles, homozygotes = 12) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0191502; MAF= 1.91502%, 567/29608 alleles, homozygotes = 10); grpmax FAF= 0.00426711.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00105174; MAF= 0.10517%, 295/280488 alleles, homozygotes = 5) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0198183; MAF= 1.98183%, 205/10344 alleles, homozygotes = 5); grpmax FAF= 0.00036814.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0018458197611292075, 34/18420 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Benign (5 clinical laboratories). (ClinVarID = 242230)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57220253, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.