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.1 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=).2 ClinVar reports this variant as Likely benign from 3 clinical laboratories (Labcorp/Invitae, Ambry Genetics, PreventionGenetics), with no pathogenic assertions from any submitter.3 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.4 Final classification: Likely Benign.
TERT
Final classification
Likely Benign
TERT c.468C>T · p.Cys156=
TERT
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.
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.
Classification rationale
PM2
BP4BP6BP7
Likely Benign
TERT c.468C>T
PM2 + BP4 + BP6 + BP7
→
Likely Benign
Gene diagram
· NM_198253.2 · variants mapped to exon structure
TERT
NM_198253.2
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 16 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
gnomAD v2.1: 1/207200 alleles (AF=4.8e-60.00048%) in European (non-Finnish) subpopulation
✓
BP4
supporting
Benign
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.
Synonymous variant (p.Cys156=) with no amino acid change.SpliceAI max delta = 0.01 (no predicted splice impact).
✓
BP6
supporting
Benign
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.
ClinVar Variation ID 570843: Likely benign.3 clinical laboratories: Labcorp/Invitae (SCV000819597)Ambry Genetics (SCV002633894)
✓
BP7
supporting
Benign
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.
Synonymous variant (p.Cys156=) in exon 2.SpliceAI max delta = 0.01: no acceptor gain/lossno donor gain/loss.
Assessed · not applied
Pathogenic
PS2
No de novo observation data are available for this variant.
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.
PS4
No case-control data or sufficient case observations demonstrating enrichment of this variant in affected individuals versus controls are 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.
PM6
No de novo observation data (with or without confirmed maternity and paternity) are available for this variant.
PP1
No segregation data are available for this variant.
PP3
No in silico tools predict a deleterious effect.
PP4
No patient phenotype or family history data specific to this variant are available for evaluation.
PP5
No reputable source has recently reported this variant as pathogenic.
Benign
BA1
Population allele frequency is ~0.0003–0.0005%, far below the 1% BA1 threshold.
BS1
Population allele frequency is ~0.0003–0.0005%, far below the 0.3% BS1 threshold for non-VCEP assessment.
BS2
No data are available demonstrating observation of this variant in a healthy adult individual for a fully penetrant disorder.
BS3
No well-established in vitro or in vivo functional studies demonstrating no deleterious effect have been identified.
BS4
No segregation data are available demonstrating lack of cosegregation with disease in affected family members.
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.
BP5
No data are available demonstrating this variant in a case with an alternate molecular basis for disease.
N/A · 5
PVS1 · PS1 · PM5 · PP2 · BP1
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
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.
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).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031%
· 5 / 1,590,360
0 hom · FAF 8e-05%
0 hom · FAF 8e-05%
Remaining individuals 1 / 61,928 |
0.0016% |
European (non-Finnish) 4 / 1,176,258 |
0.00034% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.00048%
· 1 / 207,200
0 hom
0 hom
European (non-Finnish) 1 / 92,522 |
0.0011% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 4 PMIDs not cited in assessment
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR