NM_198253.2:c.2283C>T

TERT · NP_937983.2:p.(Ser761=) · NM_198253.2

GRCh37: chr5:1278759 G>A · GRCh38: chr5:1278644 G>A

Gene: TERT Transcript: NM_198253.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(Ser761=)

gnomAD AF

0.000203840377495031 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): allele frequency 0.0275% is below the 0.1% ceiling with zero homozygotes.

BP4 (Supporting): SpliceAI max delta 0.011 predicts no splice impact (below the 0.1 threshold).

Overall: Variant of Uncertain Significance - one supporting pathogenic (PM2) and one supporting benign (BP4) criterion conflict and match no ACMG/AMP combination rule.

Final determination: Under the generic ACMG/AMP 2015 combination rules (Richards et al., PMID:25741868), the single pathogenic-supporting criterion PM2 and the single benign-supporting criterion BP4 are conflicting and together meet none of the Pathogenic, Likely Pathogenic, Benign, or Likely Benign thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Not applicable: as a synonymous (silent) change, this variant triggers no null-variant mechanism such as nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: the variant is synonymous, so no altered amino acid exists to compare against a previously established pathogenic change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband or parental genotype data exist to evaluate a de novo occurrence with confirmed parentage.
PS3	Not assessed	Not assessed: no functional assay (e.g., telomerase activity or splicing/minigene analysis) for this exact variant was available.
PS4	Not assessed	Not assessed: no case-control or cohort prevalence data exist for this variant; the single COSMIC occurrence is somatic, not germline.	generic_acmg_combination_rules
PM1	N/A	Not applicable: as a synonymous change, no altered residue exists to evaluate for mutational hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): highest observed allele frequency 0.0275% (gnomAD v4.1 NFE) is ~3.6x below the 0.1% ceiling, with zero homozygotes.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no proband, pedigree, or phase data exist to evaluate trans configuration with a pathogenic allele.	clinvar gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM4	N/A	Not applicable: the synonymous change does not alter protein length, leaving nothing for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue, so there is no prior pathogenic missense to compare against.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no source reports an assumed (unconfirmed) de novo occurrence of this variant.
PP1	Not assessed	Not assessed: no family or pedigree testing exists, so zero informative meioses can be counted.
PP2	N/A	Not applicable: as a synonymous change, no missense variant exists for the gene's missense-constraint properties to apply to.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.011 is far below the 0.2 splice-altering cutoff, and no missense predictors apply to this synonymous change.	spliceai pvs1_variant_assessment generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family-history information exists to evaluate disease specificity.	generic_acmg_combination_rules
PP5	Not met	Not met: no ClinVar expert-panel pathogenic assertion exists; only three ordinary laboratory submissions, all Likely benign.	generic_acmg_combination_rules clinvar
BA1	Not met	Not met: highest allele frequency 0.0275% is 36x below the 1% stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: highest allele frequency 0.0275% is ~11x below the 0.3% threshold for frequencies exceeding disease expectation.	gnomad_v2 gnomad_v4 gnomad_canada clinvar generic_acmg_combination_rules
BS2	Not met	Not met: no homozygotes are observed in any population cohort, and TERT disorders are adult-onset with incomplete penetrance.	gnomad_v2 gnomad_v4 gnomad_canada clinvar generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no functional study of this variant exists; the SpliceAI no-impact prediction alone is not functional evidence.
BS4	Not assessed	Not assessed: no affected family member tested and found not to carry the variant has been reported.
BP1	N/A	Not applicable: as a synonymous change, this is not a missense variant in a gene with a truncating disease mechanism.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no cis/trans phase information with a pathogenic variant exists.	clinvar gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BP3	N/A	Not applicable: the variant is not an in-frame insertion/deletion in a repetitive region, so there is nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): SpliceAI max delta 0.011 is below the 0.1 threshold, predicting no impact on splicing for this synonymous variant.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband-level molecular data exist to establish an alternate molecular basis of disease.	generic_acmg_combination_rules
BP6	Not met	Not met: no ClinVar expert-panel benign classification exists; the Likely benign label comes only from ordinary laboratory submissions.	generic_acmg_combination_rules clinvar
BP7	Not assessed	Not assessed: no nucleotide conservation score is available, and the splice prediction is already counted under BP4.	spliceai pvs1_variant_assessment generic_acmg_combination_rules

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.