NM_198253.2:c.2097C>T

TERT · NP_937983.2:p.(Ala699=) · NM_198253.2

GRCh37: chr5:1279439 G>A · GRCh38: chr5:1279324 G>A

Gene: TERT Transcript: NM_198253.2

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP7 supporting benign

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(Ala699=)

gnomAD AF

0.008989709289639542 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The TERT c.2097C>T (p.Ala699=) variant has been reported in ClinVar as benign.

This variant is common in population databases, with AF 1.11328% in gnomAD v2.1, AF 0.89897% in gnomAD v4.1, and AF 1.28122% in gnomAD-Canada; the highest observed East Asian frequencies are 8.10613% in gnomAD v2.1 and 5.10623% in gnomAD v4.1, which is above benign frequency thresholds.

As a synonymous change, available in silico splicing evidence does not support RNA disruption; SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.

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 synonymous variant does not create a nonsense, frameshift, or canonical +/-1,2 splice-site change, so the generic PVS1 loss-of-function framework does not apply.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 is not applicable because this is a synonymous change and no alternate nucleotide change producing the same amino acid substitution is relevant here.
PS2	Not assessed	No confirmed de novo data were identified for this variant.
PS3	Not assessed	No well-established functional study demonstrating a damaging effect for this specific variant was identified.	oncokb
PS4	Not met	Available evidence does not show enrichment of this variant in affected individuals over controls, and the variant is common in population databases, which argues against PS4.	clinvar gnomad_v2 gnomad_v4 gnomad_canada
PM1	Not met	This variant is not located in a demonstrated mutational hotspot or other established critical functional region without benign variation.	hotspots
PM2	Not met	This variant is not absent from population databases; it is present at AF 1.11328% in gnomAD v2.1, AF 0.89897% in gnomAD v4.1, and AF 1.28122% in gnomAD-Canada, so PM2 is not met.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic variant for a recessive disease mechanism.
PM4	N/A	PM4 is not applicable because this variant does not change protein length or disrupt an in-frame region.
PM5	N/A	PM5 is not applicable because this is not a missense change, and the PM5 review artifact did not support classic same-residue comparator use for this variant.	pm5_candidates
PM6	Not assessed	No assumed de novo evidence was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	PP2 is not applicable because this is not a missense variant.
PP3	Not met	Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.00.	spliceai
PP4	Not assessed	No phenotype-specific evidence was identified linking this variant to a highly specific TERT-related clinical presentation in a way that supports PP4.
PP5	Not assessed	External database assertions alone were not used as independent pathogenic evidence for this criterion.	clinvar
BA1	Met	Population frequency is above the benign stand-alone threshold of 1%. This variant is present at AF 1.11328% in gnomAD v2.1 and AF 1.28122% in gnomAD-Canada, with much higher East Asian frequencies of 8.10613% in gnomAD v2.1 and 5.10623% in gnomAD v4.1.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Met	Population frequency is above the strong benign threshold of 0.3%. This variant is present at AF 1.11328% in gnomAD v2.1, AF 0.89897% in gnomAD v4.1, and AF 1.28122% in gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Although the variant is seen in many population samples, no disease-specific framework was identified establishing that observation in unaffected adults is sufficient for BS2 in TERT-related disease.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study demonstrating a benign effect for this specific variant was identified.	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant.
BP1	N/A	BP1 is not applicable because this is not a missense variant.
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis for a recessive disorder.
BP3	N/A	BP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region.
BP4	N/A	BP4 was not used because this is a synonymous variant; benign computational support for lack of splice effect is more appropriately captured under BP7.	spliceai
BP5	Not assessed	No alternate molecular explanation was identified that would make this variant an incidental finding relative to a fully explained phenotype.
BP6	Not assessed	External benign assertions were not used as independent evidence for this criterion.	clinvar
BP7	Met	This is a synonymous variant, NP_937983.2:p.(Ala699=), and available splicing prediction does not support RNA disruption. SpliceAI shows a maximum delta score of 0.00, which is below a level suggesting splice impact.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.