About TERT
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TERT c.2781A>G, p.(Leu927=)
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, with an allele frequency of 0.00149% (24/1,613,722 alleles) in gnomAD v4.1 and absent from gnomAD v2.1, well below the 0.1% PM2 threshold.
Benign criteria applied · 1
BP7Supporting
BP7 · supporting
NM_198253.2:c.2781A>G is a synonymous variant (p.Leu927=). SpliceAI predicts no impact on splicing with a maximum delta score of 0.00, consistent with a silent variant unlikely to alter gene product or splicing.
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, BP7 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
24 / 1,613,722 alleles
gnomAD v4.1: 24 / 1,613,722 alleles. Recorded AF 1.48725e-05. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
2 Uncertain significance · 2 Likely benign · 1 Benign.
Context only
ClinVar ↗
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
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 · 11 not met · 9 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.2781A>G (p.Leu927=) in TERT is a synonymous variant with extremely low population frequency (gnomAD v4.1 AF = 0.00149%, 24/1,613,722 alleles; absent from gnomAD v2.1), meeting PM2 at supporting strength.
SpliceAI predicts no splicing alteration (max delta = 0.00), consistent with a silent variant, meeting BP7 at supporting_benign strength.
PVS1 is not met as this synonymous variant does not qualify as a null variant per the ClinGen SVI PVS1 decision framework (PMC6185798). Computational evidence is insufficient for PP3 or BP4. No variant-specific functional studies, case-control data, segregation data, or de novo observations are available. ClinVar reports mixed classifications (Uncertain significance, Likely benign, Benign) from single submitters without expert panel consensus.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP7), the net evidence weight is indeterminate. This variant is classified as a Variant of Uncertain Significance.
No criteria match.
Met · 2
PM2 SupportingThis variant is extremely rare in population databases, with an allele frequency of 0.00149% (24/1,613,722 alleles) in gnomAD v4.1 and absent from gnomAD v2.1, well below the 0.1% PM2 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=1.49e-05 (24/1
- 613
- 722 alleles
- 0 homozygotes)
- grpmax FAF=9.53e-06
- gnomAD v2.1: absent.
Sources
BP7 SupportingNM_198253.2:c.2781A>G is a synonymous variant (p.Leu927=). SpliceAI predicts no impact on splicing with a maximum delta score of 0.00, consistent with a silent variant unlikely to alter gene product or splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00: no predicted acceptor gain
- acceptor loss
- donor gain
- or donor loss
- synonymous variant p.(Leu927=).
Still missing
- Nucleotide-level conservation data not assessed to exclude evolutionary constraint at this position.
Sources
Not met · 11 · evaluated, threshold not reached
PVS1 NM_198253.2:c.2781A>G is a synonymous variant (p.Leu927=) that does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Synonymous variant predicted to produce wild-type protein NP_937983.2:p.(Leu927=)
- no splice consensus disruption.
Still missing
- No CSPEC/VCEP PVS1 framework available for TERT
- generic fallback applied.
Sources
PS4 No case-control data demonstrate significantly increased prevalence of this variant in affected individuals. ClinVar-associated PMIDs (20301408, 20301779, 26389258, 26389333) are GeneReviews/PDQ summaries that do not mention this specific variant. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 350629 has 5 germline submissions but no case-control statistics or variant-specific patient counts.
Still missing
- No cohort or case-control studies evaluating NM_198253.2:c.2781A>G in TERT-associated disease.
Sources
PM1 This variant does not lie in a statistically significant mutational hotspot per hotspot analysis, and no critical functional domain has been specifically implicated at codon 927. Details ▾Hide ▴
Evidence considered
- Hotspots analysis: residue not significant
- exact variant not listed as a hotspot mutation.
Still missing
- No domain-level functional evidence implicating Leu927 as a critical residue.
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). REVEL, BayesDel, and HCI prior scores are unavailable for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no predicted splice alteration)
- REVEL/BayesDel/HCI prior not available.
Still missing
- REVEL and BayesDel scores not available
- conservation data not assessed.
Sources
PP5 Of the four ClinVar-associated PMIDs flagged as PP5 candidates (GeneReviews/PDQ summaries: 20301408, 20301779, 26389258, 26389333), none mention NM_198253.2:c.2781A>G. These are gene-level reviews of TERT-associated disorders and do not constitute variant-specific evidence. Details ▾Hide ▴
Evidence considered
- Four GeneReviews/PDQ PMIDs from ClinVar reviewed
- none contain variant-specific mention of c.2781A>G.
Still missing
- No reputable source has asserted this variant as pathogenic.
Sources
BA1 The population allele frequency of 0.00149% in gnomAD v4.1 is far below the 1% BA1 threshold. Details ▾Hide ▴
BS1 The population allele frequency of 0.00149% in gnomAD v4.1 is far below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 1.49e-05 (0.00149%)
- well below 0.3% threshold.
Sources
BS2 No homozygotes have been observed in gnomAD v4.1 (24 heterozygous alleles among 1,613,722 total alleles), failing to meet the requirement for observation in a healthy adult homozygous state. Details ▾Hide ▴
BP4 Insufficient computational evidence to meet the 'multiple lines' threshold. SpliceAI predicts no splicing impact (delta = 0.00), but REVEL, BayesDel, and nucleotide conservation scores are unavailable for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- REVEL/BayesDel/HCI prior not available
- conservation data absent.
Still missing
- Missing REVEL
- BayesDel
- and conservation data needed to establish multiple lines of benign computational evidence.
Sources
BP6 ClinVar contains one benign and two likely benign single-submitter classifications, but these lack expert panel review or a published assertion from a reputable source with unavailable supporting evidence. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 350629: 1 Benign (Illumina)
- 2 Likely benign (Ambry Genetics
- Labcorp/Invitae)
- all single-submitter
- no expert panel review.
Still missing
- No expert panel or published reputable source asserting benign classification with unavailable evidence.
Sources
PS5 No reputable source has recently reported this variant as pathogenic. ClinVar aggregate classification is Uncertain significance with mixed submissions (2 US, 2 LB, 1 B); no expert panel consensus exists. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 350629: 5 single-submitter classifications
- none from expert panel
- mixed interpretations without pathogenic consensus.
Still missing
- No expert panel or reputable source asserting pathogenicity.
Sources
Not assessed · 9 · no assessment recorded
PS2 No de novo observation with confirmed paternity and maternity has been reported for this variant. Details ▾Hide ▴
Still missing
- No family studies or de novo reports identified.
PS3 No well-established in vitro or in vivo functional studies supporting a damaging effect have been identified for this specific synonymous variant. Details ▾Hide ▴
Evidence considered
- OncoKB labels this variant as Unknown Oncogenic Effect with no variant-specific functional PMIDs.
Still missing
- No functional assay data available for NP_937983.2:p.(Leu927=).
PM6 No de novo observation (with or without confirmed paternity) has been reported for this variant. Details ▾Hide ▴
Still missing
- No de novo reports identified in ClinVar or literature.
PP1 No co-segregation data with disease in multiple affected family members has been reported for this variant. Details ▾Hide ▴
Still missing
- No family segregation studies available.
PP4 No patient phenotype or family history data are available to determine whether the clinical presentation is highly specific for a TERT-associated disorder. Details ▾Hide ▴
Still missing
- No proband phenotype or family history provided.
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect have been identified for this specific synonymous variant. Details ▾Hide ▴
Still missing
- No functional assay data available for NP_937983.2:p.(Leu927=).
BS4 No family segregation data are available to evaluate lack of segregation with disease. Details ▾Hide ▴
Still missing
- No family studies available.
BP2 No data on observation in trans with a dominant pathogenic variant are available. Details ▾Hide ▴
Still missing
- No phase or trans-configuration data available.
BP5 No data on observation in a case with an alternate molecular basis for disease are available. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis data available.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ASynonymous variant with no amino acid change; PS1 requires a different nucleotide change producing the same amino acid change as an established pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ASkipped per directive; TERT-associated disorders follow autosomal dominant or autosomal recessive inheritance patterns requiring specific trans/phase data not available for this assessment. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per directive; this variant is a single-nucleotide substitution, not a protein-length-altering change. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ASynonymous variant with no amino acid change; cannot evaluate same-residue pathogenic missense comparator per PM5 semantics. Details ▾Hide ▴
No further detail was recorded.
PP2 N/APP2 is specific to missense variants in genes with a low rate of benign missense variation. NM_198253.2:c.2781A>G is a synonymous (silent) variant, not a missense change. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 is specific to missense variants in genes where truncating variants are the primary disease mechanism. NM_198253.2:c.2781A>G is a synonymous variant, not a missense change. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ASkipped per directive; this variant is a substitution, not an in-frame indel in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- TERT
- Transcript
- NM_198253.2
- Coding (HGVS c.)
- NM_198253.2:c.2781A>G
- Protein (HGVS p.)
- NP_937983.2:p.(Leu927=)
- GRCh38
- chr5:1264466 T>C
- GRCh37
- chr5:1264581 T>C
- ClinVar
- 350629
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
24 / 1,613,722 alleles
AF 1.49e-05 · 0 homozygotes · FAF 9.53e-06
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.5e-05 · 24 / 1,613,722 alleles · 0 hom · FAF 9.5e-06
| Remaining individuals4 / 62,478 | 6.4e-05 |
| South Asian2 / 91,094 | 2.2e-05 |
| European (non-Finnish)18 / 1,180,036 | 1.5e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.48725e-05; MAF= 0.00149%, 24/1613722 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 6.40225e-05; MAF= 0.00640%, 4/62478 alleles, homozygotes = 0); grpmax FAF= 9.53e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingNM_198253.2:c.2781A>G is a synonymous variant (p.Leu927=). SpliceAI predicts no impact on splicing with a maximum delta score of 0.00, consistent with a silent variant unlikely to alter gene product or splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00: no predicted acceptor gain
- acceptor loss
- donor gain
- or donor loss
- synonymous variant p.(Leu927=).
Still missing
- Nucleotide-level conservation data not assessed to exclude evolutionary constraint at this position.
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). REVEL, BayesDel, and HCI prior scores are unavailable for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no predicted splice alteration)
- REVEL/BayesDel/HCI prior not available.
Still missing
- REVEL and BayesDel scores not available
- conservation data not assessed.
Sources
BP4 Insufficient computational evidence to meet the 'multiple lines' threshold. SpliceAI predicts no splicing impact (delta = 0.00), but REVEL, BayesDel, and nucleotide conservation scores are unavailable for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- REVEL/BayesDel/HCI prior not available
- conservation data absent.
Still missing
- Missing REVEL
- BayesDel
- and conservation data needed to establish multiple lines of benign computational evidence.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
5 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 20301408 ↗Pulmonary Fibrosis Predisposition Overview.Adam MP et al. · 1993GeneReviews overview of pulmonary fibrosis genetic predisposition. Discusses TERT as a gene associated with familial pulmonary fibrosis at the gene level. NM_198253.2:c.2781A>G (p.Leu927=) was not identified in this source.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 related telomere biology disorders. Discusses TERT pathogenic variants in the context of telomere biology disorders. NM_198253.2:c.2781A>G (p.Leu927=) was not identified in this source.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. Covers TERT in the context of cancer predisposition syndromes at the gene level. NM_198253.2:c.2781A>G (p.Leu927=) was not identified in this source.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. Discusses TERT promoter mutations in melanoma but does not reference coding-region variants. NM_198253.2:c.2781A>G (p.Leu927=) was not identified in this source.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Describes the Sherloc refinement of the ACMG-AMP variant classification framework. This is a methods paper and does not discuss any specific TERT variant. NM_198253.2:c.2781A>G (p.Leu927=) was not identified in this source. This paper was cited by a ClinVar submitter (Labcorp/Invitae, SCV001654691) as a classification methodology reference.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
24 / 1,613,722 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
2 Uncertain significance · 2 Likely benign · 1 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/350629/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-1264581-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-1264466-T-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-1264466-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_198253.2%3Ac.2781…
- OncoKB ↗www.oncokb.org/gene/TERT/L927=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TERT+c.2781A%3EG
- 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= 1.48725e-05; MAF= 0.00149%, 24/1613722 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 6.40225e-05; MAF= 0.00640%, 4/62478 alleles, homozygotes = 0); grpmax FAF= 9.53e-06.
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) and as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 350629)
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.