About TERT
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TERT c.1234C>T, p.(His412Tyr)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 0
Benign evidence criteria: 6
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 6
BA1Stand alone
BA1 · stand alone
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.
BS1Strong
BS1 · strong
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.
BS2Strong
BS2 · strong
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.
BS3Strong
BS3 · strong
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.
BP4Supporting
BP4 · supporting
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.
BP6Supporting
BP6 · supporting
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.
Recorded classification: 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.
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
7,043 / 1,561,382 alleles
gnomAD v4.1: 7,043 / 1,561,382 alleles. Recorded AF 0.00451075. Recorded homozygote count 20.
gnomAD 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.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.004125950054288816, 76/18420 alleles, homozygotes = 0).
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
17 reported laboratory submissions
11 Likely benign · 4 Benign · 1 Uncertain significance · 1 Uncertain Significance. ClinVar API review status: criteria provided, conflicting classifications.
Functional evidence
Statement recorded
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
7 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57234896, n = 7 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 6 met · 17 not met · 1 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_198253.2:c.1234C>T (p.His412Tyr) in TERT is classified as Benign.
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.
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.
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).
Multiple clinical laboratories in ClinVar (15 of 17) classify this variant as Likely benign or Benign, providing supporting evidence for a benign interpretation (BP6).
SpliceAI predicts no splicing impact (max delta 0.01), and BayesDel score (0.139) is consistent with a benign interpretation (BP4).
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).
No criteria match.
Met · 6
BA1 Stand aloneThe 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 ASJ AF = 1.88% (>1%)
- gnomAD v4.1 ASJ AF = 1.85% (>1%)
- with 3 ASJ homozygotes in each dataset.
Still missing
- Patient ancestry unknown
- BA1 applied using ASJ subpopulation frequency. If patient is not of Ashkenazi Jewish ancestry
- global AF does not reach BA1 threshold.
Sources
BS1 StrongThe 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 0.325%
- v4.1 AF = 0.451%
- both >0.3% BS1 threshold.
Sources
BS2 StrongThe 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. Details ▾Hide ▴
Evidence considered
- 5 homozygotes in gnomAD v2.1
- 20 homozygotes in gnomAD v4.1. Inconsistent with a dominant highly penetrant disorder.
Sources
BS3 StrongThe 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. Details ▾Hide ▴
Evidence considered
- 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.
Sources
BP4 SupportingSpliceAI 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 (no splice impact)
- BayesDel 0.139 (non-deleterious)
- functional data confirms normal activity.
Sources
BP6 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- 15 clinical laboratories in ClinVar classify as Likely benign or Benign
- strong clinical consensus supports benign interpretation.
Sources
Not met · 17 · evaluated, threshold not reached
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. The only nucleotide change producing p.His412Tyr is c.1234C>T. Details ▾Hide ▴
Evidence considered
- c.1234C>T is the only nucleotide change encoding p.His412Tyr at this codon.
PS2 No de novo data available for this variant. No parentage or family-based testing reported in the provided evidence. Details ▾Hide ▴
Evidence considered
- No de novo observation in the provided evidence.
Still missing
- De novo testing data not provided.
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. This evidence supports a benign interpretation (BS3) rather than a pathogenic one (PS3). No functional data suggest a damaging effect. Details ▾Hide ▴
Evidence considered
- Direct telomerase activity assays in PMID:23901009 show H412Y retains high enzymatic activity (1.07–1.20× wild-type)
- contradicting a pathogenic functional effect.
Sources
PS4 No case-control data demonstrating enrichment of this variant in affected individuals versus controls. The variant is common in population databases, which is inconsistent with a pathogenic role in a rare disease. Details ▾Hide ▴
Evidence considered
- Variant present in gnomAD at population frequency too high for a rare Mendelian disease variant.
Still missing
- No case-control study available.
Sources
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. No statistically significant mutational hotspot at this residue per cancerhotspots.org. Details ▾Hide ▴
Evidence considered
- Variant is in the RT domain but common in population
- not a cancerhotspots.org significant hotspot.
Sources
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). These frequencies exceed the PM2 threshold of <0.1% for non-VCEP generic ACMG application. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 0.325%
- gnomAD v4.1 AF = 0.451%
- both >0.1% PM2 threshold.
Sources
PM5 No same-residue pathogenic comparator variant identified. Automated PM5 candidate harvesting found no candidates, and manual review confirms no alternate amino acid change at position 412 with an established pathogenic classification. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic comparator identified at His412.
Sources
pm5_candidates
PM6 No de novo observation reported for this variant. No parentage data available. Details ▾Hide ▴
Evidence considered
- No de novo data provided.
Still missing
- De novo testing data not provided.
PP1 No cosegregation data available for this variant. No family studies reported in the provided evidence. Details ▾Hide ▴
Evidence considered
- No family cosegregation data available.
Still missing
- Cosegregation data not provided.
PP2 TERT harbors numerous benign missense variants in population databases. The gene does not exhibit a low rate of benign missense variation; PP2 requires a gene where missense variants are a common mechanism of disease and benign missense variation is rare. Details ▾Hide ▴
Evidence considered
- Multiple benign TERT missense variants observed in population databases
- H412Y itself is common.
Sources
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). Additionally, direct functional data (PMID:23901009) demonstrates normal telomerase activity, contradicting a deleterious in silico prediction. Details ▾Hide ▴
Evidence considered
- REVEL 0.672
- BayesDel 0.139
- SpliceAI max delta 0.01. Mixed predictions
- functional data contradicts deleterious prediction.
Sources
PP5 ClinVar classification for this variant is Likely benign/Benign by 15 of 17 clinical laboratories, with the remaining 2 reporting Uncertain significance. No expert panel has classified this variant as pathogenic. The ClinVar review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold for PP5 application. Details ▾Hide ▴
Evidence considered
- ClinVar consensus is benign (15 labs LB/B)
- review status is 1-star
- not 3-star expert panel
- not eligible for PP5.
Sources
BS4 No cosegregation data available to assess lack of segregation with disease. Details ▾Hide ▴
Evidence considered
- No family cosegregation data available.
Still missing
- Cosegregation data not provided.
BP1 TERT-related disease is caused by both missense and truncating variants. BP1 requires that the gene primarily harbors truncating pathogenic variants, which is not the case for TERT. Multiple pathogenic missense variants in TERT are documented in association with telomere biology disorders. Details ▾Hide ▴
Evidence considered
- TERT disease mechanism includes both missense and truncating pathogenic variants
- BP1 does not apply.
Sources
pvs1_gene_context
BP2 No evidence that this variant has been observed in trans with a known pathogenic TERT variant. No phase data available. Details ▾Hide ▴
Evidence considered
- No trans phase data available.
Still missing
- Phase data not provided.
BP5 No evidence that this variant has been observed in a case with an alternative molecular basis for disease. No such data provided. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data provided.
Still missing
- Alternate molecular basis data not provided.
PS5 No established pathogenic variant with a different nucleotide change resulting in the same amino acid substitution at this position has been identified. p.His412Tyr can only arise from c.1234C>T; alternative nucleotide changes at codon 412 produce different amino acid substitutions (His412Asn, His412Asp, His412Pro, His412Arg, His412Leu). Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change at codon 412 producing p.His412Tyr
- PS5 by definition requires the same amino acid change from a different nucleotide.
Not assessed · 1 · no assessment recorded
PP4 Patient phenotype information is not provided in the case evidence. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No patient phenotype data provided for assessment.
Still missing
- Patient phenotype data not available in the case materials.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_198253.2:c.1234C>T is a missense variant (p.His412Tyr). It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant
- excluded from generic PVS1 framework.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/APM3 is for recessive disorders (variant detected in trans with a pathogenic variant). No phase data provided, and this criterion was pre-skipped. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein-length changes (in-frame deletions/insertions, stop-loss). This is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without a known function. This is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_198253.2:c.1234C>T is a missense variant (p.His412Tyr), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants only.
Identifiers
- Gene
- TERT
- Transcript
- NM_198253.2
- Coding (HGVS c.)
- NM_198253.2:c.1234C>T
- Protein (HGVS p.)
- NP_937983.2:p.(His412Tyr)
- GRCh38
- chr5:1293652 G>A
- GRCh37
- chr5:1293767 G>A
- ClinVar
- 12730
- COSMIC
- COSV57234896
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TERT
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
7,043 / 1,561,382 alleles
AF 0.00451 · 20 homozygotes · FAF 0.00505
gnomAD v2.1
646 / 198,904 alleles
AF 0.00325 · 5 homozygotes · FAF 0.00417
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.0045 · 7043 / 1,561,382 alleles · 20 hom · FAF 0.005
| Ashkenazi Jewish531 / 28,714 | 0.0183 hom |
| Remaining individuals330 / 60,588 | 0.00543 hom |
| European (non-Finnish)5947 / 1,153,206 | 0.005213 hom |
| Middle Eastern9 / 5,998 | 0.00151 hom |
| European (Finnish)66 / 59,060 | 0.0011 |
| Admixed American52 / 51,682 | 0.001 |
| African/African American60 / 74,082 | 0.00081 |
| South Asian48 / 84,842 | 0.00057 |
0 alternate alleles recorded in 2 other groups: Amish, East Asian.
gnomAD v2.1
AF 0.0032 · 646 / 198,904 alleles · 5 hom · FAF 0.0042
| Ashkenazi Jewish167 / 8,868 | 0.0193 hom |
| European (non-Finnish)384 / 83,108 | 0.00462 hom |
| Remaining individuals19 / 5,602 | 0.0034 |
| Admixed American32 / 26,264 | 0.0012 |
| European (Finnish)22 / 19,266 | 0.0011 |
| African/African American14 / 18,080 | 0.00077 |
| South Asian8 / 23,596 | 0.00034 |
0 alternate alleles recorded in 1 other group: East Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD 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.
gnomAD 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.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.004125950054288816, 76/18420 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.672
- BayesDel
- 0.139
How the predictions were used
BP4 SupportingSpliceAI 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 (no splice impact)
- BayesDel 0.139 (non-deleterious)
- functional data confirms normal activity.
Sources
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). Additionally, direct functional data (PMID:23901009) demonstrates normal telomerase activity, contradicting a deleterious in silico prediction. Details ▾Hide ▴
Evidence considered
- REVEL 0.672
- BayesDel 0.139
- SpliceAI max delta 0.01. Mixed predictions
- functional data contradicts deleterious prediction.
Sources
BP7 N/ANM_198253.2:c.1234C>T is a missense variant (p.His412Tyr), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants only.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.672. BayesDel score = 0.139499.
6 paper records listed. 1 cited in the classification.
Cited in the classification
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PMID 23901009 ↗Many disease-associated variants of hTERT retain high telomerase enzymatic activity.Zaug AJ et al. · 2013 OctZaug 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.→ BS3 Names this variant
Source detail
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.
Other recorded publications
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PMID 18042801 ↗Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene.Du HY et al. · 2008Du et al. describe two families with dyskeratosis congenita and compound heterozygous TERT mutations (one family: c.1892G>A and c.2105C>G; second family: c.1892G>A and c.2692C>T). The specific variant NM_198253.2:c.1234C>T (p.His412Tyr) is not among the mutations characterized in this study.Does not name this variant
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PMID 18931339 ↗TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements.Du HY et al. · 2009Du et al. screened TERC and TERT genes in bone marrow failure patients. The specific variant NM_198253.2:c.1234C>T (p.His412Tyr) was not identified in the abstract; the study focused on identifying novel TERT mutations in an unselected BMF population.Does not name this variant
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PMID 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.Whole-exon sequencing study of 33 human myeloma cell lines identifying mutations in DNA repair and regulation pathways. TERT gene and NM_198253.2:c.1234C>T (p.His412Tyr) were not discussed or identified in this paper.Does not name this variant
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PMID 15814878 ↗Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia.Yamaguchi H et al. · 2005Yamaguchi et al. identified TERT mutations in patients with apparently acquired aplastic anemia. The specific variant NM_198253.2:c.1234C>T (p.His412Tyr) was not identified in the abstract. This paper is cited in the Zaug 2013 functional study as a source of prior H412Y functional data, but variant-specific content could not be confirmed from the abstract alone.Does not name this variant
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PMID 22138009 ↗NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology.NCCN Task Force report evaluating clinical utility of tumor markers across multiple cancer types (glioma, breast, colon, lung, prostate, AML). TERT, telomerase, and NM_198253.2:c.1234C>T (p.His412Tyr) are not discussed or identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
7,043 / 1,561,382 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
11 Likely benign · 4 Benign · 1 Uncertain significance · 1 Uncertain Significance
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/12730/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-1293767-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-1293652-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-1293652-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_198253.2%3Ac.1234…
- OncoKB ↗www.oncokb.org/gene/TERT/H412Y
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=127097362
- Cancer hotspots ↗www.cancerhotspots.org/
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= 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.
gnomAD 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.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.004125950054288816, 76/18420 alleles, homozygotes = 0).
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
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Neutral.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57234896, n = 7 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.