NM_198253.2:c.875C>T

TERT · NP_937983.2:p.(Thr292Met) · NM_198253.2

GRCh37: chr5:1294126 G>A · GRCh38: chr5:1294011 G>A

Gene: TERT Transcript: NM_198253.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(Thr292Met)

gnomAD AF

6.302245616157949e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_198253.2:c.875C>T (p.Thr292Met) is a missense variant in exon 2 of TERT. TERT is associated with autosomal dominant and recessive telomere biology disorders including dyskeratosis congenita, bone marrow failure, and pulmonary fibrosis.

This variant is extremely rare in population databases, absent from gnomAD v2.1 and gnomAD-Canada, and present at an allele frequency of 6.3e-7 (1/1,586,736 alleles, 0 homozygotes) in gnomAD v4.1, satisfying PM2 at supporting strength.

Multiple lines of computational evidence suggest this variant is tolerated: BayesDel score is -0.237 (benign range), REVEL score is 0.296 (below the 0.5 pathogenicity threshold), and SpliceAI predicts no splicing impact (max delta = 0.01), collectively satisfying BP4 at supporting strength.

No functional studies, case-control data, segregation analysis, or de novo observations were identified for this variant. ClinVar reports two clinical laboratory submissions, both classifying the variant as Uncertain significance. All reviewed publications discuss TERT at the gene level and do not mention this specific variant.

Under the generic ACMG/AMP 2015 classification framework, the variant NM_198253.2:c.875C>T (p.Thr292Met) is classified as a Variant of Uncertain Significance (VUS), with balanced pathogenic (PM2_supporting) and benign (BP4_supporting) evidence. Additional evidence such as functional characterization, segregation data, or case-control studies would be needed to reclassify this variant.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	This is a missense variant (c.875C>T, p.Thr292Met) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence of a different nucleotide change at the same position (c.875) resulting in the same amino acid change (p.Thr292Met) that has been classified as pathogenic. PS1 requires an alternate substitution at the same nucleotide position producing the same protein change with established pathogenicity.
PS2	Not met	No de novo occurrence data are available for this variant. PS2 requires confirmed de novo observation in a patient with the disease and no family history.
PS3	Not met	No variant-specific functional studies have been identified for NM_198253.2:c.875C>T. OncoKB reports unknown oncogenic effect with no variant-specific reviewed functional evidence. COSMIC reports two somatic occurrences (COSV99716364), but somatic counts alone do not constitute functional evidence. No systematic range characterization (tiling screen, saturation mutagenesis, or truncation series) includes this residue. Reviewed ClinVar-associated and PVS1 gene-context publications confirmed none contain functional data for this variant.	oncokb
PS4	Not met	No significant enrichment of this variant in affected individuals compared to controls has been demonstrated. The variant is present at extremely low frequency in gnomAD v4.1 (1/1,586,736 alleles; AF=6.3e-7). Two clinical laboratories have reported this variant in ClinVar as VUS, but these submissions do not provide case counts or case-control evidence. The ClinVar-associated publications are GeneReviews and PDQ summaries that discuss TERT-related disorders at the gene level without mentioning this variant.	clinvar gnomad_v4
PS5	Not met	No evidence of a different pathogenic missense variant at codon 292 of TERT with a different amino acid change. PS5 requires an established pathogenic variant at the same residue with a different amino acid substitution.
PM1	Not met	The variant affects codon 292, which lies within the TEN (telomerase essential N-terminal) domain of TERT. However, this residue is not within a statistically significant mutational hotspot as determined by cancerhotspots.org, and no residue-specific functional or clinical evidence establishes this position as a critical residue. The TEN domain is a large functional domain, and PM1 at domain level typically requires a mutational hotspot or well-established critical functional sub-region. This missense variant does not remove or structurally disrupt the domain.	oncokb
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and is present at an extremely low frequency in gnomAD v4.1 (AF=6.3e-7, 1/1,586,736 alleles, 0 homozygotes). The highest subpopulation frequency is in South Asian (AF=1.14e-5). These frequencies are well below the 0.1% threshold for PM2 in genes associated with rare disease.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants with different amino acid changes and confirmed pathogenicity were identified; automated PM5 candidate harvesting was unable to confirm classic PM5 semantics for this variant.	pm5_candidates
PM6	Not met	No de novo data are available for this variant. PM6 requires a confirmed de novo observation with maternity and paternity confirmed. Neither of the two ClinVar submissions (Labcorp/Invitae, Ambry Genetics) reports de novo status.	clinvar
PP1	Not met	No segregation data are available for this variant. PP1 requires cosegregation of the variant with disease in multiple affected family members.
PP2	Not met	No gene-specific missense constraint data (HCI prior) are available for TERT. PP2 requires demonstration that the gene has a low rate of benign missense variation (high missense Z-score) and that missense variants are a common mechanism of disease. TERT is known to harbor both pathogenic missense and truncating variants, but without explicit constraint metrics, PP2 cannot be applied.
PP3	Not met	Multiple in silico tools do not support a damaging effect for this variant. REVEL score is 0.296 (below the commonly used 0.5 threshold for pathogenicity). BayesDel score is -0.237 (in the benign range). SpliceAI predicts no splicing impact (max delta = 0.01). These computational predictions do not meet the threshold for PP3, which requires multiple lines of computational evidence supporting a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data are available to evaluate whether the clinical presentation is specific for TERT-related disease (telomere biology disorders including dyskeratosis congenita, bone marrow failure, pulmonary fibrosis). PP4 requires the patient's phenotype or family history to be highly specific for the gene/disease.
PP5	Not met	This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (Labcorp/Invitae and Ambry Genetics). Neither has classified the variant as pathogenic or likely pathogenic. The ClinVar-associated publications (GeneReviews, PDQ summaries) are gene-level reviews and do not specifically assess or classify this variant. PP5 requires a reputable source to have classified the variant as pathogenic.	clinvar
BA1	Not met	The allele frequency in gnomAD v4.1 is 6.3e-7 (0.000063%), which is far below the 1% threshold required for BA1. This variant is effectively absent from population databases.	gnomad_v4
BS1	Not met	The allele frequency in gnomAD v4.1 is 6.3e-7 (0.000063%), which is far below the 0.3% threshold required for BS1. This variant is effectively absent from population databases.	gnomad_v4
BS2	Not met	Only one heterozygous carrier has been observed in gnomAD v4.1 (1/1,586,736 alleles, 0 homozygotes). BS2 requires observation in a homozygous state in healthy adults, or at a frequency too high for a fully penetrant dominant disorder. The single heterozygous observation does not meet this threshold.	gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no damaging effect have been identified for this variant. BayesDel predicts a benign score (-0.237) and REVEL is low (0.296), but computational predictions alone are insufficient for BS3, which requires experimental functional data showing no deleterious effect in a validated assay system.	bayesdel revel
BS4	Not met	No segregation data are available to evaluate lack of cosegregation with disease. BS4 requires observation that the variant does not segregate with disease in affected family members.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where the primary disease mechanism is through truncating (loss-of-function) variants. TERT is associated with telomere biology disorders through both pathogenic missense and truncating germline variants. Pathogenic missense variants in TERT are well-established in the literature, including in the TEN and RT domains. Therefore, BP1 does not apply to TERT missense variants.	pvs1_gene_context
BP2	Not met	No evidence of this variant occurring in trans with a known pathogenic variant in TERT. BP2 requires observation in trans with a pathogenic variant in a recessive disorder, or in cis with a pathogenic variant in any inheritance pattern.
BP4	Met	Multiple lines of computational evidence suggest this variant is tolerated and does not impact gene product function. BayesDel predicts a benign score (-0.237), REVEL score is low (0.296, below the 0.5 threshold for deleterious prediction), and SpliceAI predicts no splicing impact (max delta = 0.01). The convergence of independent computational tools toward a benign prediction satisfies BP4 at supporting level.	bayesdel revel spliceai
BP5	Not met	BP5 applies when a variant is found in a case with an alternate molecular basis for disease. No such alternate molecular explanation has been documented for the case(s) with this variant. Insufficient clinical context is available to evaluate this criterion.
BP6	Not met	This variant is reported in ClinVar as Uncertain significance (VUS) by two clinical laboratories (Labcorp/Invitae and Ambry Genetics). BP6 requires classification as benign or likely benign by a reputable source. No reputable source has classified this variant as benign or likely benign.	clinvar
BP7	N/A	This is a missense variant (c.875C>T, p.Thr292Met), not a synonymous variant. BP7 applies only to synonymous (silent) variants for which splicing algorithms predict no impact on the splice consensus sequence or a new cryptic splice site.

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