Variant classification summary

NM_198253.2:c.3184G>A

TERT · NP_937983.2:p.(Ala1062Thr) · NM_198253.2

GRCh37: chr5:1254594 C>T · GRCh38: chr5:1254479 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.(Ala1062Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TERT NM_198253.2:c.3184G>A (p.Ala1062Thr) variant has been reported in ClinVar, where most submissions classify it as benign or likely benign.

2

This variant is common in population databases, with allele frequencies of 1.24601% in gnomAD v2.1 and 1.94967% in gnomAD v4.1, which are above the benign stand-alone threshold of 1.0% and above the BS1 threshold of 0.3%.

3

In silico prediction does not support a damaging effect, with REVEL 0.207, BayesDel -0.373519, and SpliceAI maximum delta score 0.01 predicting no significant splice impact.

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, not a nonsense, frameshift, or canonical splice-site variant. Generic PVS1 is therefore not applicable for this change.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework
PS1	Not assessed	No evidence was identified that another nucleotide change causing the same amino acid substitution has already been established as pathogenic or likely pathogenic.
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.
PS3	Not assessed	Published TERT functional literature was identified, but the reviewed materials did not provide a well-established variant-specific functional assay result for p.(Ala1062Thr) that could be used to support a damaging effect.	PMID:15814878 PMID:19147845 PMID:19760749 PMID:19796246 PMID:21520173 clinvar
PS4	Not met	Although this variant has been reported in disease literature and ClinVar, it is also common in population databases, with gnomAD v2.1 AF 1.24601% and gnomAD v4.1 AF 1.94967%, both well above the PM2 rarity threshold of 0.1%. These frequencies do not support enrichment in affected individuals sufficient for PS4.	clinvar gnomad_v2 gnomad_v4 PMID:19147845 PMID:19760749 PMID:19796246
PM1	Not met	This variant does not lie in a statistically significant hotspot, and no well-established critical region without benign variation was identified for residue Ala1062 from the reviewed sources.	hotspots
PM2	Not met	This variant is not absent or rare in population databases. Its gnomAD v2.1 allele frequency is 1.24601% and its gnomAD v4.1 allele frequency is 1.94967%, both above the PM2 threshold of 0.1%.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified for occurrence in trans with a pathogenic variant in a recessive disease context.
PM4	N/A	This variant is a missense substitution and does not cause a protein length change.
PM5	Not assessed	No reviewed evidence established a different pathogenic missense change at the same amino acid residue that could support PM5.
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	No gene-specific evidence was identified that TERT is a gene in which missense variation is a common established mechanism and benign missense variation is uncommon enough to support PP2.
PP3	Not met	Available computational evidence does not support a deleterious effect. REVEL is 0.207, BayesDel is -0.373519, and SpliceAI shows a maximum delta score of 0.01, which predicts no significant splice impact.	revel bayesdel spliceai
PP4	Not assessed	No case-specific phenotype information was identified that is highly specific for a single genetic etiology and sufficient to support PP4.
PP5	N/A	PP5 is not applied because this criterion relies on external assertions without independently reviewable evidence.
BA1	Met	This variant is common in population databases. The gnomAD v2.1 allele frequency is 1.24601% and the gnomAD v4.1 allele frequency is 1.94967%, both above the benign stand-alone threshold of 1.0%.	gnomad_v2 gnomad_v4
BS1	Met	Population frequency is greater than expected for a pathogenic TERT germline variant. The gnomAD v2.1 allele frequency is 1.24601% and the gnomAD v4.1 allele frequency is 1.94967%, both above the BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	This variant is observed in multiple homozygotes in gnomAD, but the reviewed materials did not provide gene-specific penetrance or phenotype context needed to determine whether BS2 should be applied for TERT-related disease.	gnomad_v2 gnomad_v4
BS3	Not assessed	Published TERT functional literature was identified, but the reviewed materials did not provide a well-established variant-specific functional assay result for p.(Ala1062Thr) demonstrating normal function that would support BS3.	PMID:15814878 PMID:19147845 PMID:19760749 PMID:19796246 PMID:21520173 clinvar
BS4	Not assessed	No non-segregation data were identified for this variant.
BP1	N/A	BP1 is not applicable because missense variation in TERT has been reported in disease-associated contexts, so this is not a gene where only truncating variants are clearly established as pathogenic.	PMID:15814878 PMID:17460043 PMID:19147845 PMID:19760749 PMID:19796246 PMID:21520173
BP2	Not assessed	No phase data were identified to determine whether this variant occurs in trans with a pathogenic variant for a dominant disorder or in cis with another variant.
BP3	N/A	This is not an in-frame insertion or deletion in a repetitive region.
BP4	Met	Multiple computational results support a benign effect. REVEL is 0.207 and BayesDel is -0.373519, both favoring a tolerated missense change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01.	revel bayesdel spliceai
BP5	Not assessed	No alternate molecular explanation for a specific reported phenotype was identified for the individual under evaluation.
BP6	N/A	BP6 is not applied because this criterion relies on external assertions without independently reviewable evidence.
BP7	N/A	BP7 is not applicable because this is a missense variant rather than a synonymous or intronic variant.

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