NM_198253.2:c.1234C>T

TERT · NP_937983.2:p.(His412Tyr) · NM_198253.2

GRCh37: chr5:1293767 G>A · GRCh38: chr5:1293652 G>A

Gene: TERT Transcript: NM_198253.2

Final call

Benign

BA1 stand-alone benign BS1 strong BS2 strong BS3 strong BP4 supporting BP6 supporting

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(His412Tyr)

gnomAD AF

0.004510747530072717 (v4.1)

ClinVar

Likely benign

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	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.
PS2	Not met	No de novo data available for this variant. No parentage or family-based testing reported in the provided evidence.
PS3	Not met	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.	PMID:23901009
PS4	Not met	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.	gnomad_v2 gnomad_v4
PS5	Not met	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).
PM1	Not met	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.	gnomad_v2 gnomad_v4
PM2	Not met	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.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is for recessive disorders (variant detected in trans with a pathogenic variant). No phase data provided, and this criterion was pre-skipped.
PM4	N/A	PM4 applies to protein-length changes (in-frame deletions/insertions, stop-loss). This is a single-nucleotide missense substitution.
PM5	Not met	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.	pm5_candidates
PM6	Not met	No de novo observation reported for this variant. No parentage data available.
PP1	Not met	No cosegregation data available for this variant. No family studies reported in the provided evidence.
PP2	Not met	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.	gnomad_v2 gnomad_v4
PP3	Not met	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.	revel bayesdel spliceai PMID:23901009
PP4	Not assessed	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.
PP5	Not met	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.	clinvar
BA1	Met	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 gnomad_v4
BS1	Met	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 gnomad_v4
BS2	Met	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.	gnomad_v2 gnomad_v4
BS3	Met	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.	PMID:23901009
BS4	Not met	No cosegregation data available to assess lack of segregation with disease.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	No evidence that this variant has been observed in trans with a known pathogenic TERT variant. No phase data available.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without a known function. This is a single-nucleotide missense substitution.
BP4	Met	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 revel bayesdel PMID:23901009
BP5	Not met	No evidence that this variant has been observed in a case with an alternative molecular basis for disease. No such data provided.
BP6	Met	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.	clinvar
BP7	N/A	NM_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.

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