Variant Report |

LYFE Sciences · Project HERA

Variant Interpretation · Classification Report

Generated: 2026-07-09

Case ID: NM_198253.2_c.2765T_A_20260709_092822

Framework: ACMG/AMP 2015

Variant classification summary

TERT · NP_937983.2:p.(Met922Lys) · NM_198253.2

GRCh37: chr5:1264597 A>T · GRCh38: chr5:1264482 A>T

Gene: TERT Transcript: NM_198253.2

Final call

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(Met922Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_198253.2:c.2765T>A (p.Met922Lys) is a missense variant in TERT, a gene in which loss-of-function is an established mechanism for autosomal dominant telomere biology disorders including dyskeratosis congenita and familial melanoma.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency 0%), meeting PM2 at supporting strength.

Computational predictors are inconclusive or lean benign: REVEL score 0.409 (below 0.5 threshold), BayesDel score -0.101837 (benign range), and SpliceAI max delta 0.00 (no predicted splice impact). PP3 is not met.

This variant has not been reported in ClinVar, COSMIC, or the published literature; no functional, segregation, or case-control data are available.

PM2 (supporting) is the only met criterion. No pathogenic criteria above supporting strength are met, and no benign criteria are triggered. Under the ACMG/AMP 2015 generic classification framework, a single supporting criterion is insufficient to reach Likely Pathogenic. This variant is classified as a Variant of Uncertain Significance (VUS).

Final determination:

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	Missense variant (p.Met922Lys) does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants); not eligible for PVS1 under the ClinGen SVI generic PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No different pathogenic missense change at amino acid position 922 (Met922) has been identified in ClinVar or published literature.	clinvar
PS2	Not met	No de novo observation data available for this variant.
PS3	Not met	No well-established functional studies demonstrate a damaging effect for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence.	oncokb
PS4	Not met	No case-control data available comparing variant prevalence in affected versus unaffected individuals.
PS5	Not met	No data meeting PS5 criteria; variant is absent from ClinVar and no published reports of segregation or de novo occurrence.	clinvar
PM1	Not met	Not located in a statistically significant mutational hotspot (CancerHotspots.org) and no domain-level functional evidence has been presented to support PM1 at this residue.
PM2	Met	Absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting the allele frequency threshold of <0.1% for PM2 under generic ACMG/AMP guidelines.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic variant at the same amino acid residue (Met922) with a different amino acid change has been identified in ClinVar; PM5 candidate search returned zero same-residue candidates.	pm5_candidates clinvar
PM6	Not met	No de novo observation data available for this variant.
PP1	Not met	No co-segregation data available for this variant in affected families.
PP2	Not met	TERT missense constraint data (HCI prior) is not available for this gene; insufficient data to assess whether TERT has a low rate of benign missense variation and high rate of pathogenic missense variation.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.409 is below the 0.5 pathogenicity threshold, BayesDel score -0.101837 falls in the benign range, and SpliceAI predicts no splicing impact (max delta = 0.00).	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data available for this variant.
PP5	Not met	Not reported as pathogenic by a reputable source; this variant is absent from ClinVar.	clinvar
BA1	Not met	Allele frequency is 0% across all gnomAD populations, well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency is 0% across all gnomAD populations, well below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No evidence of this variant observed in a homozygous state in healthy adults.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate a benign effect for this variant; no variant-specific functional data is available.	oncokb
BS4	Not met	No segregation data available for this variant in affected families.
BP1	Not met	Although TERT loss-of-function is a supported germline disease mechanism, TERT-related telomere biology disorders are caused by both truncating and missense pathogenic variants. The evidence does not demonstrate that TERT disease is primarily caused by truncating variants to the exclusion of missense changes.	pvs1_gene_context
BP2	Not met	No evidence of this variant observed in trans with a known pathogenic variant.
BP4	Not met	Computational evidence is mixed and does not provide multiple lines of strong support for a benign impact. REVEL 0.409 is intermediate, BayesDel -0.101837 weakly supports benign, and SpliceAI max delta 0.00 indicates no splicing effect. This does not meet the threshold for BP4, which requires multiple lines of computational evidence all suggesting no impact.	revel bayesdel spliceai
BP5	Not met	No evidence that this variant is found in a case with an alternate molecular basis for disease.
BP6	Not met	Not reported as benign by a reputable source; this variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies only to synonymous variants. NM_198253.2:c.2765T>A is a missense variant (p.Met922Lys).

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