NM_198253.2:c.2509C>T

TERT · NP_937983.2:p.(Leu837Phe) · NM_198253.2

GRCh37: chr5:1268708 G>A · GRCh38: chr5:1268593 G>A

Gene: TERT Transcript: NM_198253.2

Final call

VUS

PM2 supporting

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(Leu837Phe)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_198253.2:c.2509C>T (p.Leu837Phe) is a rare missense variant in the TERT gene that is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).

This variant has been reported in ClinVar as a Variant of Uncertain Significance by a single clinical laboratory (Labcorp/Invitae, SCV003459151).

No variant-specific functional studies, case-control data, de novo observations, segregation data, or same-residue pathogenic comparators were identified for this variant.

In silico predictions are conflicting: REVEL predicts a deleterious effect (0.735), while BayesDel predicts a benign effect (0.123), and SpliceAI predicts no splicing impact (delta = 0.00).

TERT loss-of-function is an established disease mechanism for autosomal dominant dyskeratosis congenita and related telomere biology disorders, and both truncating and missense variants have been reported as pathogenic in the literature.

Applying generic ACMG/AMP 2015 classification rules (PMID:25741868), only one supporting criterion (PM2) is met, with no benign criteria met. This is insufficient to classify as Likely Pathogenic or Likely Benign, resulting in a final classification of Variant of Uncertain Significance (VUS).

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.2509C>T is a missense variant (p.Leu837Phe) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_generic_framework
PS1	Not met	No pathogenic or likely pathogenic variant with the same amino acid change (p.Leu837Phe or another change at L837) was identified in ClinVar or the literature. No same-residue comparator exists to support PS1.	pm5_candidates
PS2	Not met	No de novo observation (with confirmed maternity and paternity) was identified for NM_198253.2:c.2509C>T in the available evidence.
PS3	Not met	No variant-specific functional data were identified for NM_198253.2:c.2509C>T (p.Leu837Phe) in the literature or through OncoKB. OncoKB classifies the variant as Unknown Oncogenic Effect, and no publication with experimental functional characterization of this variant was retrieved.	oncokb
PS4	Not met	No case-control data or statistically significant enrichment of NM_198253.2:c.2509C>T in affected individuals over controls was identified. A single ClinVar submitter classifies the variant as Uncertain significance, and no publication provides variant-specific prevalence data.	clinvar
PS5	N/A	PS5 is not a criterion defined in the generic ACMG/AMP 2015 guidelines (PMID:25741868). No CSPEC/VCEP framework with an operative PS5 rule was available for TERT.
PM1	Not met	The variant p.Leu837Phe lies in the C-terminal region of TERT but is not located in a statistically significant mutational hotspot per cancerhotspots.org, and no literature was identified that specifically characterizes position 837 as lying within a well-characterized critical functional domain where missense variants are an established disease mechanism.
PM2	Met	NM_198253.2:c.2509C>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting PM2 at supporting strength under generic ACMG/AMP with an allele frequency of 0.0 in all population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic or likely pathogenic missense variant at the same amino acid residue (p.Leu837) was identified in ClinVar. The PM5 candidate harvest returned zero same-residue comparators.	pm5_candidates
PM6	Not met	No de novo observation (without confirmed parentage) was identified for NM_198253.2:c.2509C>T in the available evidence.
PP1	Not met	No co-segregation data with disease in multiple affected family members were identified for this variant.
PP2	Not assessed	PP2 requires evidence that TERT has a low rate of benign missense variation (e.g., high missense Z-score or constraint metric). The HCI prior was not available for TERT (gene not supported), and no alternative missense constraint metric was retrieved. This criterion cannot be adjudicated without constraint data.
PP3	Not met	In silico predictions are conflicting: REVEL predicts a deleterious effect (score 0.735, above 0.5 threshold), but BayesDel predicts a benign effect (score 0.123, below the damaging threshold). SpliceAI predicts no splicing impact (max delta = 0.00). Multiple lines of computational support for a deleterious effect are not present; the conflict between REVEL and BayesDel precludes PP3 application.	revel bayesdel spliceai
PP4	Not met	No patient-specific phenotype or family history data highly specific for a TERT-related telomere biology disorder were available for this case.
PP5	Not met	No reputable source classifies NM_198253.2:c.2509C>T as pathogenic. The single ClinVar submission classifies it as Uncertain significance. PMID:20301779 (GeneReviews on Dyskeratosis Congenita) is a general gene-level review and does not specifically classify this variant. PMID:28492532 (Sherloc) is a methodology paper and does not reference this variant.	clinvar PMID:20301779
BA1	Not met	NM_198253.2:c.2509C>T is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). Allele frequency of 0.0 is far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_198253.2:c.2509C>T is absent from all population databases. Allele frequency of 0.0 is below the 0.3% BS1 threshold for non-VCEP assessment.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No evidence that NM_198253.2:c.2509C>T has been observed in a healthy adult individual for a fully penetrant disorder. Population databases show zero observations.
BS3	Not met	No well-established functional studies were identified that demonstrate NM_198253.2:c.2509C>T has no deleterious effect on protein function or splicing. No functional assay data exist for this variant.	oncokb
BS4	Not met	No segregation data in affected families are available to demonstrate lack of co-segregation with disease.
BP1	Not met	While TERT loss-of-function is an established disease mechanism for telomere biology disorders, pathogenic missense variants in TERT are also well-documented in the literature (e.g., in dyskeratosis congenita and MDS). The gene does not primarily cause disease through truncating variants only; therefore BP1 does not apply to a TERT missense variant.	pvs1_gene_context
BP2	Not met	No evidence that NM_198253.2:c.2509C>T has been observed in trans with a known dominant pathogenic variant for a fully penetrant disorder.
BP4	Not met	In silico predictions are conflicting: REVEL score of 0.735 suggests a deleterious effect, which contradicts the benign prediction from BayesDel (score 0.123). SpliceAI shows no splicing impact (delta = 0.00). BP4 requires multiple lines of computational evidence suggesting no impact on gene product; the REVEL score precludes this conclusion.	revel bayesdel spliceai
BP5	Not met	No evidence that NM_198253.2:c.2509C>T was found in a case with an alternative molecular basis for disease.
BP6	Not met	No reputable source classifies NM_198253.2:c.2509C>T as benign. ClinVar classification is Uncertain significance.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_198253.2:c.2509C>T is a missense variant (p.Leu837Phe), not a synonymous variant.
BP3	N/A	Skipped per instruction. In-frame indels in non-repeat regions: variant is a substitution, not applicable.
PM3	N/A	Skipped per instruction. Recessive disorder trans-phase observation: no such data available for this variant.
PM4	N/A	Skipped per instruction. Protein length change: variant is a missense substitution, not an in-frame indel or stop-loss.

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.