Variant classification summary

NM_198253.2:c.2517G>A

TERT · NP_937983.2:p.(Thr839=) · NM_198253.2

GRCh37: chr5:1268700 C>T · GRCh38: chr5:1268585 C>T

Gene: TERT Transcript: NM_198253.2

Final call

Benign

BS1 strong BS2 strong BP4 supporting benign BP7 supporting benign

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(Thr839=)

gnomAD AF

0.0023273514306858343 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_198253.2:c.2517G>A (p.Thr839=) is a synonymous variant in TERT exon 9.

2

This variant is common in population databases: gnomAD v2.1 AF 0.268% with 2 homozygotes, grpmax FAF 0.656% (BS1).

3

gnomAD v4.1 confirms high frequency: AF 0.233% with 16 homozygotes, grpmax FAF 0.728% (BS1).

4

Sixteen homozygotes observed in gnomAD v4.1, incompatible with a highly penetrant telomere biology disorder whether dominant or recessive (BS2).

5

Multiple in silico tools predict no functional impact: REVEL 0.176, BayesDel 0.124, SpliceAI max delta 0.00 (BP4).

6

Synonymous variant with no predicted splice alteration; SpliceAI max delta 0.00 (BP7).

7

ClinVar reports Likely benign (8 laboratories) and Benign (7 laboratories); however, review status is 1-star (criteria provided, single submitter), precluding application of BP6.

8

No functional studies, segregation data, case-control evidence, or de novo observations were identified for this variant in any reviewed source.

9

Classification: Benign. Two strong benign criteria (BS1, BS2) and two supporting benign criteria (BP4, BP7) are met. No pathogenic criteria are met.

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	NM_198253.2:c.2517G>A is a synonymous variant (p.Thr839=). SpliceAI predicts no splicing impact (max delta 0.00). Does not fall into PVS1 null-variant buckets (nonsense, frameshift, canonical ±1,2 splice).	pvs1_variant_assessment spliceai
PS1	N/A	Synonymous variant produces no amino acid change. No same-residue missense to compare with an established pathogenic variant.
PS2	N/A	No de novo data available for this variant.
PS3	Not met	No functional studies identified for NM_198253.2:c.2517G>A. Full-text review of all available publications (PMID:22138009, PMID:25741868, PMID:32171751) found no mention of this variant. OncoKB classification is 'Unknown Oncogenic Effect' with no supporting PMIDs.	oncokb PMID:22138009 PMID:25741868 PMID:32171751
PS4	Not met	No case-control data demonstrating enrichment of this variant in affected individuals. Publications flagged for PS4 (PMID:26389258, PMID:26389333, PMID:32171751, PMID:33661592) are PDQ summaries and clinical practice guidelines for unrelated genes; none mention NM_198253.2:c.2517G>A. The high population frequency (AF 0.27%) further argues against case enrichment.	gnomad_v2 gnomad_v4 PMID:26389258 PMID:26389333 PMID:32171751 PMID:33661592
PS5	N/A	Synonymous variant produces no amino acid change. PS5 requires a different nucleotide change leading to the same amino acid change as an established pathogenic missense variant.
PM1	Not met	Synonymous variant. No significant hotspot at this residue (cancerhotspots.org: not significant). PM1 applies to missense variants in critical functional domains or statistically significant hotspots; a synonymous variant without splice impact does not satisfy PM1.
PM2	Not met	This variant is common in population databases. gnomAD v2.1: AF 0.268% (754/281,612 alleles, 2 homozygotes), grpmax FAF 0.656%. gnomAD v4.1: AF 0.233% (3,755/1,613,422 alleles, 16 homozygotes), grpmax FAF 0.728%. Well above the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM5	N/A	Synonymous variant with no amino acid change. PM5 candidate harvesting could not resolve residue context; no comparator pathogenic missense at this codon.	pm5_candidates
PM6	N/A	No de novo data available for this variant.
PP1	Not met	No segregation data available for this variant.
PP2	N/A	NM_198253.2:c.2517G>A is a synonymous variant, not a missense variant. PP2 applies to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	Multiple in silico tools uniformly predict a benign effect: REVEL 0.176, BayesDel 0.124, SpliceAI max delta 0.00. No computational evidence supports pathogenicity.	revel bayesdel spliceai
PP4	N/A	No patient phenotype data available for specificity assessment.
PP5	Not met	ClinVar review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel. Per PP5/BP6 rule, supporting-level evidence requires 3-star EP status. Additionally, ClinVar classification is Likely benign/Benign; PP5 requires a pathogenic classification from a reputable source.	clinvar
BA1	Not met	Highest subpopulation allele frequency: 0.735% (South Asian, gnomAD v2.1) and 0.777% (Ashkenazi Jewish, gnomAD v4.1). Neither exceeds the 1% BA1 (stand-alone benign) threshold.	gnomad_v2 gnomad_v4
BS1	Met	This variant is common in the general population. gnomAD v2.1 grpmax FAF is 0.656% (South Asian), and gnomAD v4.1 grpmax FAF is 0.728% (Ashkenazi Jewish). Both far exceed the 0.3% BS1 threshold. Observed in 2 homozygotes in v2.1 and 16 homozygotes in v4.1, confirming this is a common benign polymorphism.	gnomad_v2 gnomad_v4
BS2	Met	Observed in 16 homozygotes in gnomAD v4.1 and 2 homozygotes in gnomAD v2.1. Homozygous occurrence in a general population database is incompatible with a highly penetrant telomere biology disorder whether inherited in a dominant or recessive pattern.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no damaging effect on protein function or splicing for this specific variant. While in silico predictions are uniformly benign (see BP4), experimental functional evidence was not identified.	PMID:25741868
BS4	N/A	No family segregation data available to assess lack of co-segregation with disease.
BP1	N/A	NM_198253.2:c.2517G>A is a synonymous variant, not a missense variant. BP1 applies specifically to missense variants in genes where truncating/LoF is the primary disease mechanism.
BP2	N/A	No data on observation in trans with a pathogenic variant in a fully penetrant dominant gene.
BP4	Met	Multiple in silico tools uniformly predict no impact: REVEL score 0.176 (well within benign range), BayesDel score 0.124 (benign range), and SpliceAI max delta 0.00 (no predicted splicing alteration). All computational evidence supports a benign interpretation.	revel bayesdel spliceai
BP5	N/A	No alternate molecular basis for disease has been identified in this individual.
BP6	Not met	ClinVar review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel. Per PP5/BP6 rule, supporting-level evidence requires 3-star EP status. Although 15 clinical laboratories classify this variant as Likely benign (8) or Benign (7), the absence of expert panel review precludes BP6 application.	clinvar
BP7	Met	NM_198253.2:c.2517G>A is a synonymous variant (p.Thr839=) with SpliceAI max delta score of 0.00, confirming no predicted impact on splicing. The variant does not create or disrupt a canonical splice site. BP7 is met at supporting level.	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.