NM_198253.2:c.26C>T

TERT · NP_937983.2:p.(Ala9Val) · NM_198253.2

GRCh37: chr5:1295079 G>A · GRCh38: chr5:1294964 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.(Ala9Val)

gnomAD AF

0.0 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_198253.2:c.26C>T (p.Ala9Val) in TERT is a missense variant absent from population databases (gnomAD v2.1 and v4.1, 0/1,349,032 alleles; PM2_supporting met).

Multiple in silico predictors do not support a deleterious effect on the gene product: REVEL score 0.372, BayesDel score -0.166, and SpliceAI max delta 0.01 (BP4_supporting met).

No variant-specific functional studies, case-control data, segregation data, or de novo observations have been reported for this variant.

ClinVar classification is Uncertain Significance (1 clinical laboratory, criteria provided, single submitter). No expert panel review is available.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is conflicting and insufficient to classify the variant as either pathogenic or benign.

Overall classification: Uncertain Significance (VUS) per generic ACMG/AMP 2015 framework.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination 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
BP3	N/A	BP3 applies to in-frame indels in repetitive regions; NM_198253.2:c.26C>T is a substitution variant.
PM3	N/A	PM3 applies to recessive disorders where a variant is observed in trans with a pathogenic variant; TERT-related telomere biology disorders are autosomal dominant.
PM4	N/A	PM4 applies to protein length changes (in-frame deletions/insertions, stop-loss); NM_198253.2:c.26C>T is a missense substitution.
PVS1	N/A	NM_198253.2:c.26C>T is a missense variant (p.Ala9Val); it does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence that an alternate nucleotide change at the same codon resulting in p.Ala9Val has been previously classified as pathogenic.	clinvar
PS2	Not met	No de novo data available for NM_198253.2:c.26C>T.
PS3	Not met	No variant-specific functional studies identified for NM_198253.2:c.26C>T (p.Ala9Val). OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific reviewed functional evidence.	oncokb
PS4	Not met	No case-control studies or systematic patient ascertainment data are available for NM_198253.2:c.26C>T. The variant has been reported in ClinVar as a VUS from a single clinical laboratory without accompanying phenotype data.	clinvar
PS5	N/A	PS5 is not a defined criterion in the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868); no VCEP/CSPEC-specific PS5 rule exists for TERT.	generic_acmg_combination_rules
PM1	Not met	p.Ala9Val is located at the extreme N-terminus of TERT (position 9 of 1132 amino acids), outside of characterized critical functional domains (TEN domain, TRBD, RT, CTE). Residue is not a statistically significant hotspot at cancerhotspots.org.
PM2	Met	NM_198253.2:c.26C>T is absent from gnomAD v2.1 exomes and gnomAD v4.1 (0/1,349,032 alleles), with an allele frequency well below the 0.1% threshold for PM2 application.	gnomad_v2 gnomad_v4
PM5	N/A	No pathogenic comparator variants at the same codon (Ala9) were identified; PM5 candidate search returned zero same-residue candidates.	pm5_candidates
PM6	Not met	No de novo observations have been reported for NM_198253.2:c.26C>T.
PP1	Not met	No family segregation data are available for NM_198253.2:c.26C>T.
PP2	Not met	No missense constraint score is available for TERT (HCI prior not supported for this gene). Without evidence of a low rate of benign missense variation, PP2 cannot be applied.
PP3	Not met	In silico predictors do not support a deleterious effect: REVEL score 0.372 is below the typical pathogenic threshold (0.5), BayesDel score -0.166 is negative (benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.01).	revel bayesdel spliceai
PP4	Not met	No patient phenotype information is available to assess whether this variant was identified in a proband with a phenotype specific for TERT-related telomere biology disorders.
PP5	Not met	ClinVar classification for variant 2934760 is Uncertain Significance from a single clinical laboratory (criteria provided, single submitter). PP5 requires a pathogenic classification from a reputable source (≥3-star expert panel) — this submission does not meet that threshold.	clinvar
BA1	Not met	Allele frequency is 0% in gnomAD v4.1 (0/1,349,032 alleles), well below the BA1 threshold of 1%.	gnomad_v4
BS1	Not met	Allele frequency is 0% in gnomAD, well below the BS1 threshold of 0.3%.	gnomad_v4
BS2	Not met	No data available on observation of this variant in healthy adult controls for a fully penetrant disorder.
BS3	Not met	No well-established functional studies demonstrate that NM_198253.2:c.26C>T has no damaging effect on protein function or splicing.
BS4	Not met	No segregation data are available to assess non-segregation of this variant with disease in affected families.
BP1	Not met	TERT is associated with disease through both loss-of-function and missense mechanisms; pathogenic missense variants in TERT are well-documented. BP1 is reserved for genes where only truncating variants cause disease.	pvs1_gene_context
BP2	Not met	No data on observation of this variant in trans with a pathogenic variant in a fully penetrant dominant disorder. Additionally, TERT-related disorders are primarily autosomal dominant.
BP4	Met	Multiple lines of computational evidence suggest no deleterious effect: REVEL score 0.372 (below pathogenic threshold), BayesDel score -0.166 (negative/benign-leaning), and SpliceAI predicts no splice impact (max delta 0.01).	revel bayesdel spliceai
BP5	Not met	No evidence that an alternate molecular basis for disease has been identified in a case carrying this variant.
BP6	Not met	ClinVar classification for variant 2934760 is Uncertain significance, not benign, from a single submitter (1-star). BP6 requires a benign classification from a reputable source (≥3-star expert panel).	clinvar
BP7	N/A	NM_198253.2:c.26C>T is a missense variant (p.Ala9Val), not a silent/synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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