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.1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency 0%), meeting PM2 at supporting strength.2 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.3 This variant has not been reported in ClinVar, COSMIC, or the published literature; no functional, segregation, or case-control data are available.4 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).5
TERT
Final classification
Unclassified
TERT c.2765T>A · p.Met922Lys
TERT
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.
Classification rationale
PM2
Unclassified
TERT c.2765T>A
· exon NC_000005.10
PM2
→
Unclassified
Gene diagram
· NM_198253.2 · variants mapped to exon structure
TERT
NM_198253.2
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 22 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: allele count 0absentgnomAD v4.1: allele count 0
Assessed · not applied
Pathogenic
PS1
No different pathogenic missense change at amino acid position 922 (Met922) has been identified in ClinVar or published literature.
PS2
No de novo observation data available for this variant.
PS3
No well-established functional studies demonstrate a damaging effect for this variant.
PS4
No case-control data available comparing variant prevalence in affected versus unaffected individuals.
PM1
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.
PM5
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.
PM6
No de novo observation data available for this variant.
PP1
No co-segregation data available for this variant in affected families.
PP2
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
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).
PP4
No patient phenotype or clinical data available for this variant.
PP5
Not reported as pathogenic by a reputable source; this variant is absent from ClinVar.
Benign
BA1
Allele frequency is 0% across all gnomAD populations, well below the 1% BA1 threshold.
BS1
Allele frequency is 0% across all gnomAD populations, well below the 0.3% BS1 threshold.
BS2
No evidence of this variant observed in a homozygous state in healthy adults.
BS3
No well-established functional studies demonstrate a benign effect for this variant; no variant-specific functional data is available.
BS4
No segregation data available for this variant in affected families.
BP1
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.
BP2
No evidence of this variant observed in trans with a known pathogenic variant.
BP4
Computational evidence is mixed and does not provide multiple lines of strong support for a benign impact.
BP5
No evidence that this variant is found in a case with an alternate molecular basis for disease.
BP6
Not reported as benign by a reputable source; this variant is absent from ClinVar.
N/A · 2
PVS1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
In progress — evidence not uploaded yet.
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links