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.1 SpliceAI predicts no splicing alteration (max delta = 0.00), consistent with a silent variant, meeting BP7 at supporting_benign strength.2 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.3 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.4
TERT
Final classification
VUS
PM2BP7
TERT
c.2781A>G
p.Leu927=
This variant
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.
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.
Classification rationale
PM2
BP7
VUS
TERT c.2781A>G
PM2 + BP7
→
VUS
4
generic_acmg_combination_rules
Gene diagram
· NM_198253.2 · variants mapped to exon structure
TERT
NM_198253.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
gnomAD v4.1: AF=1.49e-05 (24/1613722 alleles
✓
BP7
supporting
Benign
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.
SpliceAI max delta = 0.00: no predicted acceptor gainacceptor lossdonor gain
Assessed · not applied
· 10 not met · 9 not assessed
Pathogenic
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).
PS2
No de novo observation with confirmed paternity and maternity has been reported for this variant.
PS3
No well-established in vitro or in vivo functional studies supporting a damaging effect have been identified for this specific synonymous variant.
PS4
No case-control data demonstrate significantly increased prevalence of this variant in affected individuals.
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.
PM6
No de novo observation (with or without confirmed paternity) has been reported for this variant.
PP1
No co-segregation data with disease in multiple affected family members has been reported for this variant.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No patient phenotype or family history data are available to determine whether the clinical presentation is highly specific for a TERT-associated disorder.
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.
Benign
BA1
The population allele frequency of 0.00149% in gnomAD v4.1 is far below the 1% BA1 threshold.
BS1
The population allele frequency of 0.00149% in gnomAD v4.1 is far below the 0.3% BS1 threshold.
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.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect have been identified for this specific synonymous variant.
BS4
No family segregation data are available to evaluate lack of segregation with disease.
BP2
No data on observation in trans with a dominant pathogenic variant are available.
BP4
Insufficient computational evidence to meet the 'multiple lines' threshold.
BP5
No data on observation in a case with an alternate molecular basis for disease are available.
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.
N/A · 7
PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0015%
· 24 / 1,613,722
0 hom · FAF 0.00095%
0 hom · FAF 0.00095%
Remaining individuals 4 / 62,478 |
0.0064% |
South Asian 2 / 91,094 |
0.0022% |
European (non-Finnish) 18 / 1,180,036 |
0.0015% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
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 · 5 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