0%
TERTc.468C>TLikely benign
Print report
Variant interpretation report

TERT c.468C>T, p.(Cys156=)

NM_198253.2:c.468C>T NP_937983.2:p.(Cys156=) View identifiers
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.

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: 3
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is extremely rare in population databases. gnomAD v2.1 exomes: 1/207,200 alleles (AF=0.00048%); gnomAD v4.1: 5/1,590,360 alleles (AF=0.00031%); gnomAD-Canada: absent. All frequencies are well below the 0.1% PM2 threshold for non-VCEP assessment.

Benign criteria applied · 3
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on the gene product. This is a synonymous variant (p.Cys156=) with no predicted effect on splicing: SpliceAI max delta score = 0.01, indicating no significant alteration to splice acceptor or donor sites and no creation of a cryptic splice site.

BP6Supporting
BP6 · supporting

This variant has been reported in ClinVar as Likely benign by 3 clinical laboratories (Labcorp/Invitae, Ambry Genetics, PreventionGenetics), representing reputable clinical sources reporting the variant as benign without compelling evidence for pathogenicity.

BP7Supporting
BP7 · supporting

NM_198253.2:c.468C>T is a synonymous variant (p.Cys156=) located in exon 2 at a non-conserved nucleotide position. SpliceAI predicts no impact on splicing (max delta score = 0.01), with no predicted alteration to the splice consensus sequence and no creation of a cryptic splice site. The variant meets BP7 criteria: synonymous variant with splicing prediction algorithms predicting no impact to the splice consensus.

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: PM2 supporting, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 1 supporting + 3 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
5 / 1,590,360 alleles

gnomAD v4.1: 5 / 1,590,360 alleles. Recorded AF 3.14394e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.82625e-06; MAF= 0.00048%, 1/207200 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.08082e-05; MAF= 0.00108%, 1/92522 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions

3 Likely benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Applied · BP6 → 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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 4 met · 17 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_198253.2:c.468C>T (p.Cys156=) is a synonymous variant in exon 2 of TERT. It has been observed at extremely low frequency in population databases (gnomAD v2.1: 1/207,200 alleles; gnomAD v4.1: 5/1,590,360 alleles) and is absent from gnomAD-Canada.

SpliceAI predicts no significant splice impact (max delta score = 0.01), consistent with a synonymous variant that does not alter splicing or the encoded amino acid sequence (p.Cys156=).

ClinVar reports this variant as Likely benign from 3 clinical laboratories (Labcorp/Invitae, Ambry Genetics, PreventionGenetics), with no pathogenic assertions from any submitter.

Applying generic ACMG/AMP 2015 classification rules: 3 supporting benign criteria are met (BP4, BP6, BP7), satisfying the threshold of ≥2 supporting benign criteria for Likely Benign. One supporting pathogenic criterion (PM2) is also present but is outweighed by the preponderance of benign evidence.

Final classification: Likely Benign.

Met · 4

PM2 SupportingThis variant is extremely rare in population databases. gnomAD v2.1 exomes: 1/207,200 alleles (AF=0.00048%); gnomAD v4.1: 5/1,590,360 alleles (AF=0.00031%); gnomAD-Canada: absent. All frequencies are well below the 0.1% PM2 threshold for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 1/207
  • 200 alleles (AF=4.8e-6
  • 0.00048%) in European (non-Finnish) subpopulation
  • 0 homozygotes.
  • gnomAD v4.1: 5/1
  • 590
  • 360 alleles (AF=3.1e-6
  • 0.00031%)
  • grpmax FAF=8e-7.
  • gnomAD-Canada: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. This is a synonymous variant (p.Cys156=) with no predicted effect on splicing: SpliceAI max delta score = 0.01, indicating no significant alteration to splice acceptor or donor sites and no creation of a cryptic splice site. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Cys156=) with no amino acid change.
  • SpliceAI max delta = 0.01 (no predicted splice impact).
Still missing
  • REVEL and BayesDel scores unavailable
  • but primary BP4 evidence (synonymous + no splice impact) is sufficient.
Sources
spliceai ↗
BP6 SupportingThis variant has been reported in ClinVar as Likely benign by 3 clinical laboratories (Labcorp/Invitae, Ambry Genetics, PreventionGenetics), representing reputable clinical sources reporting the variant as benign without compelling evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 570843: Likely benign.
  • 3 clinical laboratories: Labcorp/Invitae (SCV000819597)
  • Ambry Genetics (SCV002633894)
  • PreventionGenetics (SCV004710290).
  • Review status: criteria provided
  • single submitter (2 labs)
  • no assertion criteria provided (1 lab).
Sources
clinvar ↗
BP7 SupportingNM_198253.2:c.468C>T is a synonymous variant (p.Cys156=) located in exon 2 at a non-conserved nucleotide position. SpliceAI predicts no impact on splicing (max delta score = 0.01), with no predicted alteration to the splice consensus sequence and no creation of a cryptic splice site. The variant meets BP7 criteria: synonymous variant with splicing prediction algorithms predicting no impact to the splice consensus. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Cys156=) in exon 2.
  • SpliceAI max delta = 0.01: no acceptor gain/loss
  • no donor gain/loss.
  • Position not at a canonical splice site.
Sources
spliceai ↗

Not met · 17 · evaluated, threshold not reached

PS2 No de novo observation data are available for this variant. PS2 requires confirmation of de novo occurrence with confirmed maternity and paternity. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PS3 No well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product have been identified. OncoKB classifies this variant as Unknown Oncogenic Effect with no curated PMIDs. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no functional PMIDs available.
Still missing
  • No functional assay data available for this variant.
Sources
oncokb ↗
PS4 No case-control data or sufficient case observations demonstrating enrichment of this variant in affected individuals versus controls are available. The ClinVar-associated PMIDs (20301779, 26389258, 26389333) are general GeneReviews and PDQ references that do not report variant-specific case observations. Details ▾Hide ▴
Evidence considered
  • ClinVar-associated references are general disease summaries
  • not variant-specific case reports.
Still missing
  • No variant-specific case-control or cohort data available.
PM1 This variant does not lie in a statistically significant mutational hotspot as assessed by cancerhotspots.org, nor is it located in a critical functional domain established to have low benign variation. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: residue_significant=false
  • exact_variant_listed=no.
PM6 No de novo observation data (with or without confirmed maternity and paternity) are available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PP1 No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Still missing
  • No family segregation data available.
PP3 No in silico tools predict a deleterious effect. SpliceAI predicts no significant splice impact (max delta score = 0.01). REVEL and BayesDel scores are not available for this variant. HCI prior probability is not available for TERT. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (no predicted splice impact).
  • REVEL: score not available.
  • BayesDel: score not available.
  • HCI prior: gene not supported.
Still missing
  • REVEL and BayesDel scores unavailable for this genomic position.
Sources
spliceai ↗
PP4 No patient phenotype or family history data specific to this variant are available for evaluation. PP4 requires that the variant carrier's phenotype or family history is highly specific for the disease. Details ▾Hide ▴
Still missing
  • No phenotype data available for variant carriers.
PP5 No reputable source has recently reported this variant as pathogenic. ClinVar reports Likely benign from 3 clinical laboratories (Labcorp/Invitae, Ambry Genetics, PreventionGenetics). The ClinVar-associated PMIDs (20301779, 26389258, 26389333) are GeneReviews and PDQ general references; PMID:28492532 is a classification methodology paper (Sherloc). None report this specific variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: Likely benign
  • 3 clinical laboratories. No credible pathogenic assertion found.
Sources
clinvar ↗
BA1 Population allele frequency is ~0.0003–0.0005%, far below the 1% BA1 threshold. gnomAD v4.1 total AF = 3.1e-6 (5/1,590,360 alleles). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF = 4.8e-6 (0.00048%).
  • gnomAD v4.1 AF = 3.1e-6 (0.00031%).
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Population allele frequency is ~0.0003–0.0005%, far below the 0.3% BS1 threshold for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF = 4.8e-6 (0.00048%).
  • gnomAD v4.1 total AF = 3.1e-6 (0.00031%).
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data are available demonstrating observation of this variant in a healthy adult individual for a fully penetrant disorder. The sparse gnomAD observations (1–5 alleles across millions) are insufficient to satisfy BS2 without clinical phenotype confirmation. Details ▾Hide ▴
Evidence considered
  • gnomAD alleles too sparse (1–5 total) to confidently infer healthy adult observation without phenotype data.
Still missing
  • No phenotype-confirmed healthy adult carrier data.
BS3 No well-established in vitro or in vivo functional studies demonstrating no deleterious effect have been identified. SpliceAI predicts no splice impact (max delta 0.01), but computational prediction alone does not constitute a well-established functional study for BS3. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional assays identified
  • SpliceAI prediction alone insufficient for BS3.
Still missing
  • No functional assay data demonstrating neutral effect.
BS4 No segregation data are available demonstrating lack of cosegregation with disease in affected family members. Details ▾Hide ▴
Still missing
  • No family segregation data available.
BP2 No data are available showing observation of this variant in trans with a known pathogenic dominant variant, or in cis with a pathogenic variant in a recessive gene. Details ▾Hide ▴
Still missing
  • No phase data available for this variant.
BP5 No data are available demonstrating this variant in a case with an alternate molecular basis for disease. BP5 requires observation in a well-phenotyped case where another pathogenic variant explains the phenotype. Details ▾Hide ▴
Still missing
  • No alternate-molecular-basis data available.
PS5 No reputable source has recently reported this variant as pathogenic. ClinVar classifies this variant as Likely benign across 3 clinical laboratories. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Likely benign.
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_198253.2:c.468C>T is a synonymous variant (p.Cys156=) that does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • pvs1_variant_assessment confirms variant bucket is 'other' and apply_generic_pvs1_framework is false.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ASynonymous variant with no amino acid change. PS1 requires the same amino acid change as a previously established pathogenic variant. Details ▾Hide ▴
Evidence considered
  • Synonymous change (p.Cys156=)
  • no amino acid substitution to compare.
PM5 N/ANM_198253.2:c.468C>T is a synonymous variant (p.Cys156=) with no amino acid change. PM5 requires a different pathogenic missense change at the same amino acid residue, which is not applicable to synonymous variants. Details ▾Hide ▴
Evidence considered
  • pm5_candidates.json confirms no same-residue candidates identified
  • variant produces no amino acid change.
Sources
pm5_candidates
PP2 N/ANM_198253.2:c.468C>T is a synonymous variant (p.Cys156=), not a missense variant. PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • PP2 criterion is specific to missense variation.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_198253.2:c.468C>T is a synonymous variant (p.Cys156=), not a missense variant. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • BP1 criterion is specific to missense variation.

Identifiers

Gene
TERT
Transcript
NM_198253.2
Coding (HGVS c.)
NM_198253.2:c.468C>T
Protein (HGVS p.)
NP_937983.2:p.(Cys156=)
GRCh38
chr5:1294418 G>A
GRCh37
chr5:1294533 G>A
ClinVar
570843

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 5 / 1,590,360 alleles AF 3.14e-06 · 0 homozygotes · FAF 8e-07
gnomAD v2.1 1 / 207,200 alleles AF 4.83e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 3.1e-06 · 5 / 1,590,360 alleles · 0 hom · FAF 8e-07
Remaining individuals1 / 61,928 1.6e-05
European (non-Finnish)4 / 1,176,258 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 4.8e-06 · 1 / 207,200 alleles · 0 hom
European (non-Finnish)1 / 92,522 1.1e-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= 3.14394e-06; MAF= 0.00031%, 5/1590360 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.61478e-05; MAF= 0.00161%, 1/61928 alleles, homozygotes = 0); grpmax FAF= 8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.82625e-06; MAF= 0.00048%, 1/207200 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.08082e-05; MAF= 0.00108%, 1/92522 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -363 bp
0.010
SpliceAI acceptor gainat -27 bp
0.000
SpliceAI donor lossat -39 bp
0.000
SpliceAI donor gainat +405 bp
0.000
Pangolin splice lossmagnitude shown
-0.030
Pangolin splice gain
0.030

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. This is a synonymous variant (p.Cys156=) with no predicted effect on splicing: SpliceAI max delta score = 0.01, indicating no significant alteration to splice acceptor or donor sites and no creation of a cryptic splice site. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Cys156=) with no amino acid change.
  • SpliceAI max delta = 0.01 (no predicted splice impact).
Still missing
  • REVEL and BayesDel scores unavailable
  • but primary BP4 evidence (synonymous + no splice impact) is sufficient.
Sources
spliceai ↗
BP7 SupportingNM_198253.2:c.468C>T is a synonymous variant (p.Cys156=) located in exon 2 at a non-conserved nucleotide position. SpliceAI predicts no impact on splicing (max delta score = 0.01), with no predicted alteration to the splice consensus sequence and no creation of a cryptic splice site. The variant meets BP7 criteria: synonymous variant with splicing prediction algorithms predicting no impact to the splice consensus. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Cys156=) in exon 2.
  • SpliceAI max delta = 0.01: no acceptor gain/loss
  • no donor gain/loss.
  • Position not at a canonical splice site.
Sources
spliceai ↗
PP3 No in silico tools predict a deleterious effect. SpliceAI predicts no significant splice impact (max delta score = 0.01). REVEL and BayesDel scores are not available for this variant. HCI prior probability is not available for TERT. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (no predicted splice impact).
  • REVEL: score not available.
  • BayesDel: score not available.
  • HCI prior: gene not supported.
Still missing
  • REVEL and BayesDel scores unavailable for this genomic position.
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

4 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

  • Dyskeratosis Congenita and Related Telomere Biology Disorders.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301779 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    No paper-specific finding is recorded.
    PMID 26389258 ↗
  • Genetics of Skin Cancer (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    No paper-specific finding is recorded.
    PMID 26389333 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Sherloc classification framework paper describing a comprehensive refinement of ACMG-AMP variant classification criteria. NM_198253.2:c.468C>T was not identified as a case example in this methodology paper. Cited by Labcorp/Invitae in their ClinVar submission (SCV000819597) as the classification framework used, not as variant-specific evidence.
    Does not name this variant
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 5 / 1,590,360 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar 3 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

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= 3.14394e-06; MAF= 0.00031%, 5/1590360 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.61478e-05; MAF= 0.00161%, 1/61928 alleles, homozygotes = 0); grpmax FAF= 8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.82625e-06; MAF= 0.00048%, 1/207200 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.08082e-05; MAF= 0.00108%, 1/92522 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories). (ClinVarID = 570843)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

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.