NM_198253.2:c.3334C>A

TERT · NP_937983.2:p.(Leu1112Met) · NM_198253.2

GRCh37: chr5:1253908 G>T · GRCh38: chr5:1253793 G>T

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.(Leu1112Met)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The NM_198253.2:c.3334C>A (p.Leu1112Met) missense variant in TERT is absent from large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_supporting).

Multiple in silico tools predict a benign or neutral effect: REVEL score 0.155, BayesDel score -0.27587, and SpliceAI max delta 0.00 (BP4_supporting).

This variant has been reported in ClinVar as a Variant of Uncertain Significance by two clinical laboratories (ClinVar ID 816668). No functional studies have been performed on this variant.

The variant is a missense change at a residue that is not located in a mutational hotspot or well-established critical functional domain, and no alternate pathogenic missense variant at the same codon is known.

Overall, the available evidence includes one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), yielding a net classification of Variant of Uncertain Significance under the 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
PVS1	N/A	This is a missense variant (c.3334C>A, p.Leu1112Met) in exon 16 of TERT. It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The variant bucket is 'other' per the PVS1 variant assessment framework (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	PS1 requires a different nucleotide change at the same codon resulting in the same amino acid change that is already known to be pathogenic. No such variant has been identified for codon 1112 of TERT. The PM5 candidate search found no same-residue comparator variants in ClinVar.	pm5_candidates clinvar
PS2	Not met	PS2 requires a de novo observation with both paternity and maternity confirmed. No de novo data for this variant were identified in ClinVar submissions, the literature, or any other source.	clinvar
PS3	Not met	PS3 requires well-established in vitro or in vivo functional studies supporting a damaging effect. No functional studies have been performed on this variant. The ClinVar submission from Labcorp Genetics (SCV001385529) explicitly states that functional predictions 'have not been confirmed by published functional studies.' OncoKB identified no variant-specific functional evidence.	clinvar oncokb
PS4	Not met	PS4 requires a statistically significant enrichment of the variant in affected individuals compared to controls. Two clinical laboratories have submitted this variant to ClinVar as a VUS, but no case-control data, cohort studies, or observational evidence demonstrating enrichment in affected individuals are available. The ClinVar-linked PMIDs (20301408, 20301779) are GeneReviews overviews that do not provide variant-specific case data.	clinvar PMID:20301408 PMID:20301779
PS5	Not met	PS5 requires a reputable source to have reported the variant as pathogenic without the primary evidence being available to the evaluating laboratory. ClinVar classifies this variant as Uncertain Significance, not Pathogenic. No source reports it as pathogenic.	clinvar PMID:20301408 PMID:20301779
PM1	Not met	PM1 requires the variant to be located in a mutational hotspot or critical, well-established functional domain without benign variation. The p.Leu1112Met change lies in the C-terminal region of TERT. The hotspot analysis did not identify this residue as a statistically significant mutational hotspot, and no well-defined functional domain with an established clustering of pathogenic missense variants has been demonstrated at this position.
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the generic ACMG PM2 threshold (allele frequency < 0.1%). Absence from large population databases supports pathogenicity.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue. The automated PM5 candidate search found zero same-residue comparator variants for Leu1112. No alternate pathogenic missense at codon 1112 is known.	pm5_candidates clinvar
PM6	Not met	PM6 requires a de novo observation without confirmation of paternity and maternity. No de novo data for this variant are available from any source.	clinvar
PP1	Not met	PP1 requires co-segregation of the variant with disease in multiple affected family members. No segregation data are available for this variant.	clinvar
PP2	Not met	PP2 requires the gene to have a low rate of benign missense variation and for missense variants to be a common mechanism of disease. While missense variants are a recognized disease mechanism in TERT-related telomere biology disorders, no gene-level missense constraint metric (e.g., missense Z-score, HCI prior) is available for TERT to establish a low rate of benign missense variation. The HCI prior lookup returned no data for this gene.	pvs1_gene_context
PP3	Not met	PP3 requires multiple lines of computational evidence supporting a deleterious effect on the gene or gene product. In silico predictions for this variant are not consistent with a deleterious effect: REVEL score 0.155 (below pathogenic threshold), BayesDel score -0.27587 (negative, favors benign), and SpliceAI max delta 0.00 (no splicing impact). The computational evidence does not support a pathogenic interpretation.	revel bayesdel spliceai
PP4	Not met	PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No patient-specific phenotype data are available for this case to support PP4.
PP5	Not met	PP5 requires a reputable source to have reported the variant as pathogenic, but with evidence not available to the evaluating laboratory. ClinVar classifies this variant as Uncertain significance (2 submitters). Neither ClinVar submission asserts pathogenicity. The associated PMIDs (20301408, 20301779) are GeneReviews overviews of pulmonary fibrosis predisposition and dyskeratosis congenita that do not reference this specific variant.	clinvar PMID:20301408 PMID:20301779
BA1	Not met	BA1 requires a minor allele frequency > 1% in a general population database. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF = 0.0), so BA1 does not apply.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires a minor allele frequency > 0.3% in a general population database. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF = 0.0), so BS1 does not apply.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	BS2 requires observation of the variant in a healthy adult in the homozygous state, or in the hemizygous/heterozygous state for a fully penetrant dominant disorder. The variant is absent from gnomAD, so no homozygous observations exist. The penetrance of TERT-related telomere biology disorders is not fully penetrant in a manner that would support BS2 from heterozygous observation alone.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. No functional studies have been performed on this variant. The absence of studies does not constitute evidence that the variant is benign.	clinvar oncokb
BS4	Not met	BS4 requires lack of co-segregation with disease in multiple affected family members. No segregation data are available for this variant.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. TERT-related telomere biology disorders (dyskeratosis congenita, pulmonary fibrosis, bone marrow failure) are caused by both truncating and missense variants. Pathogenic missense variants in TERT are well-documented in the literature. Therefore, BP1 does not apply.	pvs1_gene_context
BP2	Not met	BP2 requires observation of the variant in trans with a known pathogenic variant for a fully penetrant dominant disorder, or in cis with a known pathogenic variant in any inheritance pattern. No such observations exist for this variant.
BP4	Met	BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. Multiple in silico tools predict a benign or neutral effect: REVEL score 0.155 (below the 0.5 pathogenic threshold, borderline for the <0.15 benign threshold), BayesDel score -0.27587 (negative score favors benign), and SpliceAI max delta score 0.00 (predicts no splicing impact). Taken together, these computational predictions support a lack of deleterious effect.	revel bayesdel spliceai
BP5	Not met	BP5 requires the variant to be found in a case with an alternative molecular basis for disease. No such case data exist for this variant.
BP6	Not met	BP6 requires a reputable source to report the variant as benign without access to the primary data. ClinVar classifies this variant as Uncertain Significance, not Benign. No source reports it as benign.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact to the splice consensus sequence or the creation of a new splice site, and the nucleotide is not highly conserved. This is a missense variant (c.3334C>A, p.Leu1112Met), not a synonymous variant. BP7 does not apply.

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