Variant classification summary

NM_198253.2:c.835G>A

TERT · NP_937983.2:p.(Ala279Thr) · NM_198253.2

GRCh37: chr5:1294166 C>T · GRCh38: chr5:1294051 C>T

Gene: TERT Transcript: NM_198253.2

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP4 supporting benign

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(Ala279Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TERT c.835G>A (p.Ala279Thr, p.A279T) variant has been reported in ClinVar as benign by 18 clinical laboratories.

2

This variant is common in population databases, with a total allele frequency of 2.314% in gnomAD v2.1 and 2.712% in gnomAD v4.1; the highest observed population frequency is 5.889% in Finnish individuals in v2.1 and 5.675% in Finnish individuals in v4.1.

3

In silico results do not support a damaging effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.162, and BayesDel is -0.293678.

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	This variant is a missense substitution, p.(Ala279Thr), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Although loss of function is an established disease mechanism for TERT, the available generic PVS1 assessment does not support applying PVS1 to this variant.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that another nucleotide change creates the same amino acid substitution with an established pathogenic classification, so PS1 was not assessed.
PS2	Not assessed	No confirmed de novo occurrence with parental testing was identified for this variant, so PS2 was not assessed.	clinvar
PS3	Not assessed	No well-established functional study for this exact variant was identified that demonstrates a damaging effect, so PS3 was not assessed.	oncokb
PS4	Not met	Available evidence does not show enrichment of this variant in affected individuals compared with controls. This variant is common in population databases, with gnomAD total allele frequencies of 2.314% in v2.1 and 2.712% in v4.1, which argues against PS4.	gnomad_v2 gnomad_v4 clinvar
PM1	Not met	This variant has not been shown to lie in a well-established mutational hotspot or critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at residue A279.	hotspots
PM2	Not met	This variant is not absent or rare in population databases. Its allele frequency is 2.314% in gnomAD v2.1 and 2.712% in gnomAD v4.1, which is far above the usual PM2 rarity threshold of 0.1%.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified regarding occurrence of this variant in trans with a pathogenic variant in a recessive disease context, so PM3 was not assessed.
PM4	N/A	This variant is a missense substitution and does not cause a protein length change from an in-frame insertion/deletion or stop-loss event, so PM4 is not applicable.
PM5	N/A	The available review could not confirm that classic same-residue PM5 logic should be applied for this gene/framework, and no validated same-residue pathogenic comparator was established. PM5 was therefore not applied.	pm5_candidates
PM6	Not assessed	No probable de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not assessed.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	clinvar
PP2	Not assessed	No gene-specific evidence was identified showing that TERT is a gene in which pathogenic missense variation is the predominant disease mechanism with a low rate of benign missense variation, so PP2 was not assessed.
PP3	Not met	Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.162, and BayesDel is -0.293678, which together do not support PP3.	spliceai revel bayesdel
PP4	Not assessed	No phenotype data specific enough to show that the individual's presentation is highly specific for a TERT-related disorder were identified, so PP4 was not assessed.
PP5	Not assessed	PP5 was not used because no qualifying reputable-source pathogenic assertion independent of the underlying evidence review was identified.	clinvar
BA1	Met	Population frequency is above the benign stand-alone threshold. This variant is present at 2.314% in gnomAD v2.1 and 2.712% in gnomAD v4.1, both above the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Met	Population frequency is greater than expected for a pathogenic TERT variant. The allele frequency is 2.314% in gnomAD v2.1 and 2.712% in gnomAD v4.1, both above the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Although this variant is observed in many population samples, including homozygotes in gnomAD, the available data do not establish that these are well-phenotyped unaffected adults for a fully penetrant TERT-related disorder. BS2 was therefore not applied.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study for this exact variant was identified showing normal or near-normal function, so BS3 was not assessed.	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 was not assessed.	clinvar
BP1	Not met	This is a missense variant, but the available evidence does not show that missense variation in TERT is uniformly less likely to be pathogenic than truncating variation, so BP1 was not met.	pvs1_gene_context
BP2	Not assessed	No phase information or co-occurrence data with another pathogenic variant were identified, so BP2 was not assessed.
BP3	N/A	This criterion applies to in-frame insertions/deletions in repetitive regions and is not applicable to this missense substitution.
BP4	Met	Multiple computational predictors support no damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.162, and BayesDel is -0.293678, which together support BP4.	spliceai revel bayesdel
BP5	Not assessed	No evidence was identified for an alternate molecular cause that fully explains the phenotype, so BP5 was not assessed.
BP6	Not assessed	BP6 was not used because no qualifying reputable-source benign assertion independent of the underlying evidence review was established for this pass.	clinvar
BP7	N/A	This criterion applies to synonymous or certain intronic variants without predicted splice impact and is not applicable to this missense substitution.

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