NM_198253.2:c.899G>A

TERT · NP_937983.2:p.(Gly300Asp) · NM_198253.2

GRCh37: chr5:1294102 C>T · GRCh38: chr5:1293987 C>T

Gene: TERT Transcript: NM_198253.2

Final call

VUS

PM2 moderate

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(Gly300Asp)

gnomAD AF

0.0 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_198253.2:c.899G>A (p.Gly300Asp) is a rare missense variant in TERT that is absent from population databases, with 0 alleles observed across 1,571,010 alleles in gnomAD v4.1, meeting PM2 (moderate) criterion.

This variant has been reported in ClinVar as Uncertain Significance by a single clinical laboratory (Variation ID 2937435; Labcorp Genetics). The classification is based on 1-star review status and does not meet the 3-star expert panel threshold for PP5 or BP6.

In silico predictors are inconclusive: REVEL (0.283) is intermediate, BayesDel (-0.187) is marginally in the benign direction, and SpliceAI predicts no splicing impact (max delta 0.00). No consensus supports either pathogenicity (PP3) or benignity (BP4).

No functional studies (PS3/BS3), case-control data (PS4), de novo observations (PS2/PM6), co-segregation data (PP1/BS4), or same-residue pathogenic comparators (PM5/PS1) are available for this variant.

The variant is a missense substitution and does not qualify for PVS1 null-variant assessment.

Based on the available evidence, this variant meets only one moderate pathogenicity criterion (PM2). Under the ACMG/AMP 2015 scoring framework, this alone is insufficient to classify the variant as Likely Pathogenic or Pathogenic. The variant remains a Variant of Uncertain Significance.

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
PVS1	N/A	NM_198253.2:c.899G>A is a missense variant (p.Gly300Asp), not a null variant (nonsense, frameshift, or canonical splice site). The generic PVS1 framework (PMC6185798) is not applicable to missense substitutions.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence that the same amino acid change (p.Gly300Asp) resulting from a different nucleotide substitution has been previously established as pathogenic. No alternate nucleotide change at codon 300 was identified in ClinVar or the literature.	clinvar pm5_candidates
PS2	Not met	No de novo observation data for NM_198253.2:c.899G>A was identified. No family studies or de novo reports exist in the literature or ClinVar submissions.
PS3	Not met	No variant-specific functional data exists for NM_198253.2:c.899G>A (p.Gly300Asp). OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. No literature identified contains functional assay data for this variant or a systematically characterized range that includes position 300.	oncokb
PS4	Not met	No case-control or cohort data demonstrating statistically significant enrichment of NM_198253.2:c.899G>A in affected individuals compared to controls. The sole ClinVar submission is a single clinical laboratory reporting Uncertain Significance without case-level phenotype data.	clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion (PMID:25741868). No TERT-specific VCEP/CSPEC framework exists to provide a gene-specific definition for this code. Cannot adjudicate without a criterion definition.
PM1	Not met	Position p.Gly300 is not located in a statistically significant mutational hotspot (cancerhotspots.org). While TERT contains well-characterized functional domains (TEN, TRBD, RT, CTE), no domain-level evidence specific to codon 300 was identified in the provided materials to support PM1 application.
PM2	Met	NM_198253.2:c.899G>A is absent from population databases. In gnomAD v4.1, the variant has 0 alleles across 1,571,010 total alleles (AF=0.00%), meeting the PM2 threshold for absence in population controls (AF < 0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same amino acid residue (p.Gly300) was identified in ClinVar. The PM5 candidate search returned no same-residue comparator variants. A different missense change at codon 300 cannot be assessed.	pm5_candidates clinvar
PM6	Not met	No de novo observation for NM_198253.2:c.899G>A was identified in ClinVar submissions or published literature. PM6 (assumed de novo without confirmed parentage) cannot be applied.
PP1	Not met	No co-segregation data is available for NM_198253.2:c.899G>A. No family studies or segregation analyses have been reported.
PP2	Not assessed	PP2 requires demonstration that the gene has a low rate of benign missense variation and that missense variants are a common mechanism of disease. Insufficient constraint data (HCI prior not available; no missense Z-score or regional constraint metrics) to assess PP2 for TERT.
PP3	Not met	In silico predictors do not provide multiple lines of supporting evidence for pathogenicity. REVEL score is 0.283 (low/intermediate, not strongly pathogenic). BayesDel score is -0.187 (slightly in benign direction). SpliceAI predicts no splicing impact (max delta = 0.00). No consensus among predictors supports a damaging effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data is available for the proband carrying NM_198253.2:c.899G>A. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	ClinVar reports NM_198253.2:c.899G>A as Uncertain Significance (1 star, criteria provided by a single submitter). The PP5 threshold requires a 3-star expert panel classification as pathogenic. The single-submitter VUS classification does not meet criteria for PP5 at any strength level.	clinvar
BA1	Not met	NM_198253.2:c.899G>A is absent from gnomAD (0/1,571,010 alleles). Does not exceed the BA1 threshold allele frequency of 5%.	gnomad_v4
BS1	Not met	NM_198253.2:c.899G>A is absent from gnomAD (0/1,571,010 alleles). Does not exceed the BS1 threshold allele frequency of 0.3%.	gnomad_v4
BS2	Not met	No homozygous observations of NM_198253.2:c.899G>A in gnomAD or other population databases. Cannot assess BS2 (observed in a healthy adult individual in a homozygous state for a fully penetrant dominant disorder) without homozygous carriers.	gnomad_v4
BS3	Not met	No well-established functional studies demonstrate a neutral effect for NM_198253.2:c.899G>A (p.Gly300Asp). No functional data is available for this variant.	oncokb
BS4	Not met	No segregation data is available for NM_198253.2:c.899G>A. BS4 (lack of segregation in affected family members) cannot be assessed.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. TERT has both established pathogenic missense and truncating variants associated with telomere biology disorders (e.g., dyskeratosis congenita), so BP1 is not applicable.	pvs1_gene_context
BP2	Not met	No evidence that NM_198253.2:c.899G>A has been observed in trans with a known pathogenic variant in TERT for a recessive disorder. Telomere biology disorders associated with TERT are typically autosomal dominant, making BP2 generally not applicable.	pvs1_gene_context
BP3	N/A	NM_198253.2:c.899G>A is a single-nucleotide missense substitution, not an in-frame deletion or insertion in a repetitive region.
BP4	Not met	In silico predictors do not provide multiple lines of evidence suggesting no impact. REVEL score is 0.283 (intermediate, not strongly benign). BayesDel score is -0.187 (mildly in benign direction but does not reach a strong consensus). SpliceAI predicts no splicing impact. The evidence is insufficient for a BP4 designation which requires multiple lines of computational evidence suggesting no impact on the gene or gene product.	revel bayesdel spliceai
BP5	Not met	No evidence that NM_198253.2:c.899G>A has been observed in a case with an alternate molecular basis for disease. BP5 requires a variant to be found in a patient with an established alternative genetic cause of disease.
BP6	Not met	ClinVar reports NM_198253.2:c.899G>A as Uncertain Significance, not benign. The ClinVar entry has 1-star review status (criteria provided, single submitter); the 3-star expert panel threshold required for BP6 at supporting strength is not met.	clinvar
BP7	N/A	NM_198253.2:c.899G>A is a missense variant (p.Gly300Asp), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact.

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.