NM_198253.2:c.1234C>T (p.His412Tyr) in TERT is classified as Benign.1 The allele frequency in the Ashkenazi Jewish population (1.88% in gnomAD v2.1, 1.85% in gnomAD v4.1) exceeds the BA1 stand-alone benign threshold of >1%, with multiple healthy homozygotes observed.2 The overall gnomAD allele frequency (0.32–0.45%) exceeds the BS1 threshold (>0.3%), and 5–20 homozygous individuals are observed in population databases (BS2), both inconsistent with a highly penetrant dominant telomere biology disorder.3 Direct functional studies by Zaug et al. (2013) demonstrate that H412Y retains near wild-type telomerase enzymatic activity (1.07–1.20× wild-type), confirming no damaging effect on protein function (BS3).4 Multiple clinical laboratories in ClinVar (15 of 17) classify this variant as Likely benign or Benign, providing supporting evidence for a benign interpretation (BP6).5 SpliceAI predicts no splicing impact (max delta 0.01), and BayesDel score (0.139) is consistent with a benign interpretation (BP4).6 No pathogenic criteria are met: functional data contradict a damaging effect (PS3 not met), the variant is common in population databases (PM2 not met), no de novo or cosegregation evidence exists (PS2, PM6, PP1 not met), and ClinVar consensus is benign (PP5 not met).7
TERT
Final classification
Benign
TERT c.1234C>T · p.His412Tyr
TERT
NM_198253.2:c.1234C>T (p.His412Tyr) in TERT is classified as 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: BA1 stand-alone benign, BS1 strong, BS2 strong, BS3 strong, BP4 supporting, BP6 supporting; combination = 1 stand-alone benign + 3 strong benign + 2 supporting benign, which maps to Benign.
Classification rationale
BA1BS1BS2BS3BP4BP6
Benign
TERT c.1234C>T
BA1 + BS1 + BS2 + BS3 + BP4 + BP6
→
Benign
Gene diagram
· NM_198253.2 · variants mapped to exon structure
TERT
NM_198253.2
Fetching transcript structure from UCSC…
Applied criteria · 6 applied · 17 assessed
Applied · 6
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
review
Benign
The variant has an allele frequency of 1.88% (167/8,868 alleles) in the Ashkenazi Jewish population in gnomAD v2.1 and 1.85% (531/28,714 alleles) in gnomAD v4.1. This exceeds the BA1 threshold of >1%. The global gnomAD AF is 0.32–0.45% (below 1%), but the Ashkenazi Jewish subpopulation frequency exceeds the stand-alone benign threshold. Three homozygotes are observed in the ASJ population in both gnomAD versions.
gnomAD v2.1 ASJ AF = 1.88% (>1%)gnomAD v4.1 ASJ AF = 1.85% (>1%)with 3 ASJ homozygotes in each dataset.
✓
BS1
strong
Benign
The variant is present in gnomAD v2.1 at an allele frequency of 0.325% (646/198,904 alleles) and in gnomAD v4.1 at 0.451% (7,043/1,561,382 alleles). Both exceed the BS1 threshold of >0.3% for non-VCEP generic ACMG application. The variant is too common to be a cause of a rare Mendelian telomere biology disorder.
gnomAD v2.1 AF = 0.325%v4.1 AF = 0.451%both >0.3% BS1 threshold.
✓
BS2
strong
Benign
The variant is observed in the homozygous state in 5 individuals in gnomAD v2.1 and 20 individuals in gnomAD v4.1. TERT-related telomere biology disorders (dyskeratosis congenita, aplastic anemia, pulmonary fibrosis) are dominant conditions with significant morbidity; the observation of multiple healthy adult homozygotes in population databases is inconsistent with a highly penetrant pathogenic variant.
5 homozygotes in gnomAD v2.120 homozygotes in gnomAD v4.1. Inconsistent with a dominant highly penetrant disorder.
✓
BS3
strong
Benign
The exact variant (H412Y) was directly tested in well-established telomerase enzymatic activity assays by Zaug et al. (PMID:23901009). In direct primer extension and TRAP assays, H412Y demonstrated near wild-type telomerase activity (1.07 ± 0.20 and 1.20 ± 0.20 relative to wild-type in this study; previously reported values of 0.76–1.0 by Yamaguchi et al. 2005 and Du et al. 2009). The variant does not impair telomerase catalytic function, consistent with prior functional reports.
Direct telomerase activity assays in PMID:23901009 show H412Y retains high enzymatic activity (1.07–1.20× wild-type)confirming no damaging effect on protein function. Prior studies (cited within) corroborate normal activity.
✓
BP4
supporting
Benign
SpliceAI predicts no significant splicing impact for this variant (max delta score = 0.01). Multiple in silico tools do not support a deleterious effect on splicing. REVEL (0.672) is mildly elevated but BayesDel (0.139) is low, and functional data (PMID:23901009) confirms normal protein function, reinforcing the benign in silico interpretation.
SpliceAI max delta 0.01 (no splice impact)BayesDel 0.139 (non-deleterious)functional data confirms normal activity.
✓
BP6
supporting
Benign
This variant is classified as Likely benign or Benign by 15 clinical laboratories in ClinVar (11 LB, 4 B), with only 1–2 laboratories reporting Uncertain significance. The ClinVar review status is 'criteria provided, single submitter' (1-star), which falls below the 3-star expert panel threshold for automatic PP5/BP6 application per the governing framework rule; however, the strong clinical consensus across multiple independent laboratories provides supporting evidence for a benign classification.
15 clinical laboratories in ClinVar classify as Likely benign or Benignstrong clinical consensus supports benign interpretation.
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at codon 412 resulting in the same amino acid substitution (p.His412Tyr) that has been established as pathogenic.
PS2
No de novo data available for this variant.
PS3
Functional studies of H412Y in telomerase activity assays (PMID:23901009) demonstrate near wild-type enzymatic activity (1.07–1.20 relative to wild-type), indicating the variant does not impair protein function.
PS4
No case-control data demonstrating enrichment of this variant in affected individuals versus controls.
PM1
Although position 412 lies within the TERT reverse transcriptase domain, the variant is common in population databases (gnomAD AF 0.32–0.45%, with 5–20 homozygotes), indicating the domain tolerates variation at this residue.
PM2
Variant is present in gnomAD v2.1 at AF 0.325% (646/198,904 alleles) and gnomAD v4.1 at AF 0.451% (7,043/1,561,382 alleles).
PM5
No same-residue pathogenic comparator variant identified.
PM6
No de novo observation reported for this variant.
PP1
No cosegregation data available for this variant.
PP2
TERT harbors numerous benign missense variants in population databases.
PP3
In silico predictions are mixed: REVEL score is 0.672 (elevated), but BayesDel score is 0.139 (low, non-deleterious), and SpliceAI predicts no splicing impact (max delta 0.01).
PP4
Patient phenotype information is not provided in the case evidence.
PP5
ClinVar classification for this variant is Likely benign/Benign by 15 of 17 clinical laboratories, with the remaining 2 reporting Uncertain significance.
Benign
BS4
No cosegregation data available to assess lack of segregation with disease.
BP1
TERT-related disease is caused by both missense and truncating variants.
BP2
No evidence that this variant has been observed in trans with a known pathogenic TERT variant.
BP5
No evidence that this variant has been observed in a case with an alternative molecular basis for disease.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00451075; MAF= 0.45107%, 7043/1561382 alleles, homozygotes = 20) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0184927; MAF= 1.84927%, 531/28714 alleles, homozygotes = 3); grpmax FAF= 0.00504691.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.0032478; MAF= 0.32478%, 646/198904 alleles, homozygotes = 5) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0188318; MAF= 1.88318%, 167/8868 alleles, homozygotes = 3); grpmax FAF= 0.00417366.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.004125950054288816, 76/18420 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.45%
· 7043 / 1,561,382
20 hom · FAF 0.5%
20 hom · FAF 0.5%
Ashkenazi Jewish 531 / 28,714 |
1.8% 3 hom |
Remaining individuals 330 / 60,588 |
0.54% 3 hom |
European (non-Finnish) 5947 / 1,153,206 |
0.52% 13 hom |
Middle Eastern 9 / 5,998 |
0.15% 1 hom |
European (Finnish) 66 / 59,060 |
0.11% |
Admixed American 52 / 51,682 |
0.1% |
African/African American 60 / 74,082 |
0.081% |
South Asian 48 / 84,842 |
0.057% |
+ 2 not observed (Amish, East Asian)
gnomAD v2.1
0.32%
· 646 / 198,904
5 hom · FAF 0.42%
5 hom · FAF 0.42%
Ashkenazi Jewish 167 / 8,868 |
1.9% 3 hom |
European (non-Finnish) 384 / 83,108 |
0.46% 2 hom |
Remaining individuals 19 / 5,602 |
0.34% |
Admixed American 32 / 26,264 |
0.12% |
European (Finnish) 22 / 19,266 |
0.11% |
African/African American 14 / 18,080 |
0.077% |
South Asian 8 / 23,596 |
0.034% |
+ 1 not observed (East Asian)
gnomAD Canada 🇨🇦
0.41%
· 76 / 18,420
0 hom · FAF 0.42%
0 hom · FAF 0.42%
indel · split
Ashkenazi Jewish 11 / 832 |
1.3% |
European (non-Finnish) 62 / 11,740 |
0.53% |
Remaining individuals 3 / 1,138 |
0.26% |
+ 6 not observed (African/African American, Latino/Admixed American, East Asian, European (Finnish), Middle Eastern, South Asian)
ClinVar
This variant has been reported in ClinVar as Likely benign (11 clinical laboratories) and as Benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 12730)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.672. BayesDel score = 0.139499.
Functional
Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Neutral.
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; COSV57234896, n = 7 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 5 further PMIDs triaged but not cited — see Sources & References.
Many disease-associated variants of hTERT retain high telomerase enzymatic activity.
Searched
c.1234C>TH412YHis412Tyrp.His412Tyr
Found
Zaug et al. directly assayed telomerase enzymatic activity of H412Y in both direct primer extension and TRAP assays. H412Y retained near wild-type activity (1.07 ± 0.20 and 1.20 ± 0.20 relative to wild-type), consistent with prior reports. The authors noted that H412Y and three other common non-synonymous variants (S191T, A1062T, A279T) all have high enzymatic activity despite being among the most frequent TERT variants in the NHLBI Exome Sequencing Project.
Variant
✓ Names this variant — characterised directly
Applied to
→BS3 supports · met
Why
Functional data confirmed normal telomerase activity for H412Y; used as strong evidence for BS3 (benign functional data) and to refute PS3 (no damaging functional effect).
The four non-synonymous single-nucleotide variants found with highest frequency in the NHBLI Exome Sequencing Project (S191T, H412Y, A1062T and A279T; 10–275 occurrences/12 000 genes) all have high enzymatic activity in our study, and all of the deleterious variants are rare in the population.
Location Results, Table 1; Discussion, paragraph describing common variants with high activity · Context Direct primer extension assay and TRAP assay in in vitro reconstituted telomerase system; H412Y was tested alongside 22 other TERT variants. · full text
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
18042801 ↗
Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene.
ONCOKB
18931339 ↗
TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements.
ONCOKB
30545397 ↗
Whole-exon sequencing of human myeloma cell lines shows mutations related to myeloma patients at relapse with major hits in the DNA regulation and repair pathways.
ONCOKB
15814878 ↗
Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia.
CLINVAR
22138009 ↗
NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology.
CLINVAR