Classification rationale

PM2 BP4 VUS

TERT c.2283C>T synonymous · exon 6

PM2 (Supporting): allele frequency 0.0275% is below the 0.1% ceiling with zero homozygotes. BP4 (Supporting): SpliceAI max delta 0.011 predicts no splice impact (below the 0.1 threshold). Overall: Variant of Uncertain Significance - one supporting pathogenic (PM2) and one supporting benign (BP4) criterion conflict and match no ACMG/AMP combination rule.

PM2 + BP4 → VUS

Gene diagram · NM_198253.2 · variants mapped to exon structure

TERT NM_198253.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 18 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (Supporting): highest observed allele frequency 0.0275% (gnomAD v4.1 NFE) is ~3.6x below the 0.1% ceiling, with zero homozygotes.

gnomAD v4.1 (largest and most current dataset): total AF 0.00020384 (0.0204%, 329/1,614,008 alleles), NFE AF 0.00027456 (0.0275%, 324/1,180,054), grpmax FAF 0.00024924 (0.0249%), homozygotes 0 — highest population frequency 0.0275% is below the 0.1% PM2 ceiling.gnomAD v2.1: total AF 2.785e-05 (0.00279%, 7/251,342), grpmax FAF 2.856e-05, homozygotes 0 — even lower, consistent with extremely low frequency.gnomAD-Canada v1.0 (HostSeq): AF 0.00010859 (0.0109%, 2/18,418), homozygotes 0.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (Supporting): SpliceAI max delta 0.011 is below the 0.1 threshold, predicting no impact on splicing for this synonymous variant.

SpliceAI max delta score 0.011 (DS_AG=0.000, DS_AL=0.001, DS_DG=0.002, DS_DL=0.011) is below the 0.1 threshold at which the governing generic framework assigns BP4 (supporting) for synonymous/non-missense variants, and far below the 0.2 splice-altering cutoff from the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751).Governing framework (registry key 'generic_acmg_combination_rules', source basis Richards et al. 2015, PMID 25741868) operating rule for non-VCEP cases: for intronic/synonymous/non-canonical-splice-position variants use SpliceAI only; SpliceAI max delta < 0.1 -> BP4 (supporting); max delta 0.1-0.2 gray zone (neither met).REVEL score not found and BayesDel score not found in case data; aGVGD not present. Per the framework's one-mechanism rule, only the splice path is evaluated for this synonymous variant, so the absent missense predictors do not block the BP4 call.

spliceai ↗

Assessed · not applied

Pathogenic

PS2 Not assessed: no proband or parental genotype data exist to evaluate a de novo occurrence with confirmed parentage.

PS3 Not assessed: no functional assay (e.g., telomerase activity or splicing/minigene analysis) for this exact variant was available.

PS4 Not assessed: no case-control or cohort prevalence data exist for this variant; the single COSMIC occurrence is somatic, not germline.

PM3 Not assessed: no proband, pedigree, or phase data exist to evaluate trans configuration with a pathogenic allele.

PM6 Not assessed: no source reports an assumed (unconfirmed) de novo occurrence of this variant.

PP1 Not assessed: no family or pedigree testing exists, so zero informative meioses can be counted.

PP3 Not met: SpliceAI max delta 0.011 is far below the 0.2 splice-altering cutoff, and no missense predictors apply to this synonymous change.

PP4 Not assessed: no proband phenotype or family-history information exists to evaluate disease specificity.

PP5 Not met: no ClinVar expert-panel pathogenic assertion exists; only three ordinary laboratory submissions, all Likely benign.

Benign

BA1 Not met: highest allele frequency 0.0275% is 36x below the 1% stand-alone benign threshold.

BS1 Not met: highest allele frequency 0.0275% is ~11x below the 0.3% threshold for frequencies exceeding disease expectation.

BS2 Not met: no homozygotes are observed in any population cohort, and TERT disorders are adult-onset with incomplete penetrance.

BS3 Not assessed: no functional study of this variant exists; the SpliceAI no-impact prediction alone is not functional evidence.

BS4 Not assessed: no affected family member tested and found not to carry the variant has been reported.

BP2 Not assessed: no cis/trans phase information with a pathogenic variant exists.

BP5 Not assessed: no proband-level molecular data exist to establish an alternate molecular basis of disease.

BP6 Not met: no ClinVar expert-panel benign classification exists; the Likely benign label comes only from ordinary laboratory submissions.

BP7 Not assessed: no nucleotide conservation score is available, and the splice prediction is already counted under BP4.

N/A · 8 PVS1 · PS1 · PM1 · 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= 0.00020384; MAF= 0.02038%, 329/1614008 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000274564; MAF= 0.02746%, 324/1180054 alleles, homozygotes = 0); grpmax FAF= 0.00024924.

v2.1

This variant is present in gnomAD v2.1 (AF= 2.78505e-05; MAF= 0.00279%, 7/251342 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.15991e-05; MAF= 0.00616%, 7/113638 alleles, homozygotes = 0); grpmax FAF= 2.856e-05.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.02% · 329 / 1,614,008
0 hom · FAF 0.025%

European (non-Finnish) 324 / 1,180,054	0.027%
Remaining individuals 3 / 62,488	0.0048%
African/African American 2 / 74,948	0.0027%

+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0028% · 7 / 251,342
0 hom · FAF 0.0029%

European (non-Finnish)

7 / 113,638

0.0062%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

0.011% · 2 / 18,418
0 hom · FAF 0.003%

European (non-Finnish)

2 / 11,742

0.017%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories). (ClinVarID = 471859)

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57215940, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 4 PMIDs not cited in assessment

20301779 ↗ Dyskeratosis Congenita and Related Telomere Biology Disorders. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR

26389333 ↗ Genetics of Skin Cancer (PDQ®): Health Professional Version. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR