NM_198253.2:c.833C>T

TERT · NP_937983.2:p.(Pro278Leu) · NM_198253.2

GRCh37: chr5:1294168 G>A · GRCh38: chr5:1294053 G>A

Gene: TERT Transcript: NM_198253.2

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(Pro278Leu)

gnomAD AF

3.771307889576105e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_198253.2:c.833C>T (p.Pro278Leu) in TERT is a rare missense variant with extremely low population frequency (gnomAD v2.1 AF=9.83e-6, v4.1 AF=3.77e-6), meeting PM2 at supporting strength.

Multiple in silico predictors (REVEL 0.137, BayesDel -0.245, SpliceAI max delta 0.02) consistently suggest no damaging effect on the gene product, meeting BP4 at supporting benign strength.

This variant has been reported in ClinVar as Likely benign by a single clinical laboratory (Labcorp Genetics/Invitae, 1-star review status, SCV000824613). The classification and review status do not meet thresholds for PP5 or BP6 application under the 3-star expert panel requirement.

No variant-specific functional data, de novo observations, segregation data, case-control studies, or domain-level hotspot evidence were identified. OncoKB reports Unknown Oncogenic Effect. PM1 is not met as Pro278 is not in a statistically significant mutational hotspot.

PVS1 is not applicable (missense variant outside null-variant buckets). PS1, PM5, BP7, BP3, PM3, and PM4 are not applicable due to variant type or absence of required evidence patterns.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is in equipoise. The final classification under generic ACMG/AMP 2015 rules (Richards et al., PMID:25741868) is 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	Missense variant (c.833C>T, p.Pro278Leu) does not fall into null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Generic PVS1 framework is not applicable.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence of a different nucleotide change at codon 278 producing the same Pro278Leu missense change with established pathogenicity; PS1 requires a proven pathogenic same-amino-acid change via a different nucleotide variant.
PS2	Not met	No de novo occurrence data available for this variant in any publication or database.
PS3	Not met	No variant-specific functional studies identified. OncoKB reports Unknown Oncogenic Effect. In silico predictions (REVEL 0.137, BayesDel -0.245) do not support a damaging effect and do not constitute functional evidence for PS3.	oncokb revel bayesdel
PS4	Not met	No case-control data or statistically significant enrichment of this variant in affected individuals versus controls available. The variant is extremely rare in gnomAD but no disease cohort comparison exists.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not a defined criterion in the ACMG/AMP 2015 framework (Richards et al., PMID:25741868). No framework-specific PS5 definition was retrieved for this case.	generic_acmg_combination_rules
PM1	Not met	Pro278 is not located within a statistically significant mutational hotspot (cancerhotspots.org negative). No domain-level evidence was retrieved establishing that position 278 resides in a critical, well-characterized functional domain of TERT without benign variation.	oncokb
PM2	Met	This variant is extremely rare in population databases: gnomAD v2.1 allele frequency is 9.83e-6 (0.00098%, 2/203,400 alleles), v4.1 is 3.77e-6 (0.00038%, 6/1,590,960 alleles), and absent from gnomAD-Canada. All frequencies are well below the 0.1% PM2 threshold for non-VCEP frameworks.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants identified. Automated PM5 candidate harvesting found no ClinVar variants at codon 278 with established pathogenicity.	pm5_candidates
PM6	Not met	No de novo occurrence reported for this variant in any publication or database.
PP1	Not met	No segregation data available for this variant in affected families.
PP2	Not met	Insufficient data to establish that TERT has a low rate of benign missense variation. No gnomAD Z-score or missense constraint metrics were retrieved, which are required for PP2 application.
PP3	Not met	Multiple in silico predictors do not support a damaging effect: REVEL score is 0.137 (well below ~0.5 pathogenic threshold), BayesDel is -0.245 (negative score consistent with benign effect), and SpliceAI predicts no splicing impact (max delta 0.02). These tools collectively suggest the variant is tolerated.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data specific to this variant are available to assess whether the clinical presentation matches TERT-related telomere biology disorders.
PP5	Not met	ClinVar classification is Likely benign (not pathogenic) from a single submitter (Labcorp Genetics/Invitae). PP5 requires a reputable source reporting the variant as pathogenic, and supporting-level application requires 3-star expert panel review status. Neither condition is met: the classification is benign-directed and the review status is 1-star (criteria provided, single submitter).	clinvar
BA1	Not met	gnomAD allele frequencies (v2.1: 0.00098%, v4.1: 0.00038%) are well below the 1% BA1 threshold for non-VCEP frameworks. Highest subpopulation frequency is 0.00325% (v4.1 remaining individuals).	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD allele frequencies (v2.1: 0.00098%, v4.1: 0.00038%) are well below the 0.3% BS1 threshold. Highest subpopulation frequency is 0.00325% (v4.1 remaining individuals).	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations in gnomAD and no evidence that this variant has been observed in healthy adults in the context of a fully penetrant dominant disorder. Zero homozygotes across all population databases.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this variant. In silico predictions alone (REVEL 0.137, BayesDel -0.245) do not constitute BS3-level functional evidence.	revel bayesdel
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease in affected families.
BP1	Not met	TERT-related disease is known to be caused by both missense and truncating variants. BP1 applies only to genes where primarily truncating variants cause disease, which is not the case for TERT.
BP2	Not met	No observation of this variant in trans with a known pathogenic variant for a fully penetrant dominant disorder.
BP4	Met	Multiple lines of computational evidence support no impact on the gene product: REVEL score 0.137 (below pathogenic threshold), BayesDel score -0.244664 (predicts benign effect), and SpliceAI max delta 0.02 (no predicted splicing alteration).	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case where an alternative molecular basis for disease has been identified.
BP6	Not met	ClinVar review status is 1-star (criteria provided, single submitter). BP6 supporting-level application requires a 3-star expert panel classification as benign or likely benign. The single-submitter Likely benign classification from Labcorp Genetics does not meet this threshold.	clinvar
BP7	N/A	Synonymous/non-coding variant criterion. This is a missense variant (c.833C>T, p.Pro278Leu) and BP7 is not applicable.
BP3	N/A	In-frame indel criterion; this is a single-nucleotide missense substitution.
PM3	N/A	Recessive disorder criterion; TERT-related disorders exhibit dominant and recessive inheritance patterns but no in trans observations are available for this variant.
PM4	N/A	Non-repeat in-frame indel or stop-loss criterion; this is a single-nucleotide missense substitution.

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.