NM_198253.2:c.468C>T

TERT · NP_937983.2:p.(Cys156=) · NM_198253.2

GRCh37: chr5:1294533 G>A · GRCh38: chr5:1294418 G>A

Gene: TERT Transcript: NM_198253.2

Final call

Likely Benign

PM2 supporting BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(Cys156=)

gnomAD AF

3.143942252068714e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_198253.2:c.468C>T (p.Cys156=) is a synonymous variant in exon 2 of TERT. It has been observed at extremely low frequency in population databases (gnomAD v2.1: 1/207,200 alleles; gnomAD v4.1: 5/1,590,360 alleles) and is absent from gnomAD-Canada.

SpliceAI predicts no significant splice impact (max delta score = 0.01), consistent with a synonymous variant that does not alter splicing or the encoded amino acid sequence (p.Cys156=).

ClinVar reports this variant as Likely benign from 3 clinical laboratories (Labcorp/Invitae, Ambry Genetics, PreventionGenetics), with no pathogenic assertions from any submitter.

Applying generic ACMG/AMP 2015 classification rules: 3 supporting benign criteria are met (BP4, BP6, BP7), satisfying the threshold of ≥2 supporting benign criteria for Likely Benign. One supporting pathogenic criterion (PM2) is also present but is outweighed by the preponderance of benign evidence.

Final classification: Likely Benign.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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.468C>T is a synonymous variant (p.Cys156=) that does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	Synonymous variant with no amino acid change. PS1 requires the same amino acid change as a previously established pathogenic variant.
PS2	Not met	No de novo observation data are available for this variant. PS2 requires confirmation of de novo occurrence with confirmed maternity and paternity.
PS3	Not met	No well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product have been identified. OncoKB classifies this variant as Unknown Oncogenic Effect with no curated PMIDs.	oncokb
PS4	Not met	No case-control data or sufficient case observations demonstrating enrichment of this variant in affected individuals versus controls are available. The ClinVar-associated PMIDs (20301779, 26389258, 26389333) are general GeneReviews and PDQ references that do not report variant-specific case observations.
PS5	Not met	No reputable source has recently reported this variant as pathogenic. ClinVar classifies this variant as Likely benign across 3 clinical laboratories.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot as assessed by cancerhotspots.org, nor is it located in a critical functional domain established to have low benign variation.
PM2	Met	This variant is extremely rare in population databases. gnomAD v2.1 exomes: 1/207,200 alleles (AF=0.00048%); gnomAD v4.1: 5/1,590,360 alleles (AF=0.00031%); gnomAD-Canada: absent. All frequencies are well below the 0.1% PM2 threshold for non-VCEP assessment.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	NM_198253.2:c.468C>T is a synonymous variant (p.Cys156=) with no amino acid change. PM5 requires a different pathogenic missense change at the same amino acid residue, which is not applicable to synonymous variants.	pm5_candidates
PM6	Not met	No de novo observation data (with or without confirmed maternity and paternity) are available for this variant.
PP1	Not met	No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members.
PP2	N/A	NM_198253.2:c.468C>T is a synonymous variant (p.Cys156=), not a missense variant. PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism.
PP3	Not met	No in silico tools predict a deleterious effect. SpliceAI predicts no significant splice impact (max delta score = 0.01). REVEL and BayesDel scores are not available for this variant. HCI prior probability is not available for TERT.	spliceai
PP4	Not met	No patient phenotype or family history data specific to this variant are available for evaluation. PP4 requires that the variant carrier's phenotype or family history is highly specific for the disease.
PP5	Not met	No reputable source has recently reported this variant as pathogenic. ClinVar reports Likely benign from 3 clinical laboratories (Labcorp/Invitae, Ambry Genetics, PreventionGenetics). The ClinVar-associated PMIDs (20301779, 26389258, 26389333) are GeneReviews and PDQ general references; PMID:28492532 is a classification methodology paper (Sherloc). None report this specific variant as pathogenic.	clinvar
BA1	Not met	Population allele frequency is ~0.0003–0.0005%, far below the 1% BA1 threshold. gnomAD v4.1 total AF = 3.1e-6 (5/1,590,360 alleles).	gnomad_v2 gnomad_v4
BS1	Not met	Population allele frequency is ~0.0003–0.0005%, far below the 0.3% BS1 threshold for non-VCEP assessment.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available demonstrating observation of this variant in a healthy adult individual for a fully penetrant disorder. The sparse gnomAD observations (1–5 alleles across millions) are insufficient to satisfy BS2 without clinical phenotype confirmation.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no deleterious effect have been identified. SpliceAI predicts no splice impact (max delta 0.01), but computational prediction alone does not constitute a well-established functional study for BS3.
BS4	Not met	No segregation data are available demonstrating lack of cosegregation with disease in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_198253.2:c.468C>T is a synonymous variant (p.Cys156=), not a missense variant.
BP2	Not met	No data are available showing observation of this variant in trans with a known pathogenic dominant variant, or in cis with a pathogenic variant in a recessive gene.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. This is a synonymous variant (p.Cys156=) with no predicted effect on splicing: SpliceAI max delta score = 0.01, indicating no significant alteration to splice acceptor or donor sites and no creation of a cryptic splice site.	spliceai
BP5	Not met	No data are available demonstrating this variant in a case with an alternate molecular basis for disease. BP5 requires observation in a well-phenotyped case where another pathogenic variant explains the phenotype.
BP6	Met	This variant has been reported in ClinVar as Likely benign by 3 clinical laboratories (Labcorp/Invitae, Ambry Genetics, PreventionGenetics), representing reputable clinical sources reporting the variant as benign without compelling evidence for pathogenicity.	clinvar
BP7	Met	NM_198253.2:c.468C>T is a synonymous variant (p.Cys156=) located in exon 2 at a non-conserved nucleotide position. SpliceAI predicts no impact on splicing (max delta score = 0.01), with no predicted alteration to the splice consensus sequence and no creation of a cryptic splice site. The variant meets BP7 criteria: synonymous variant with splicing prediction algorithms predicting no impact to the splice consensus.	spliceai

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