NM_198253.2:c.2031C>T

TERT · NP_937983.2:p.(Gly677=) · NM_198253.2

GRCh37: chr5:1279505 G>A · GRCh38: chr5:1279390 G>A

Gene: TERT Transcript: NM_198253.2

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP7 supporting benign

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(Gly677=)

gnomAD AF

0.011282457527886768 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The TERT c.2031C>T (p.Gly677=) variant has been reported in ClinVar as benign by multiple clinical laboratories.

This variant is common in population databases, with allele frequencies above the BA1 benign threshold of 1% in gnomAD v2.1 (1.18898%), gnomAD v4.1 (1.12825%), and gnomAD-Canada (1.04812%).

This synonymous variant does not alter the encoded amino acid, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong 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	This synonymous variant does not create a premature stop, frameshift, or canonical +/-1,2 splice-site change, so the generic loss-of-function PVS1 framework does not apply.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 is for a different nucleotide change producing the same amino acid substitution as a known pathogenic variant, and this variant is synonymous with no amino acid substitution.
PS2	Not assessed	No confirmed de novo data were identified for this variant.
PS3	Not assessed	No validated functional studies demonstrating a damaging effect of this specific variant were identified.	oncokb
PS4	Not assessed	No case-control or case-enrichment data showing this variant is more common in affected individuals than in controls were identified.	clinvar
PM1	Not met	This variant was not identified in a statistically significant mutational hotspot or other established critical functional region without benign variation.	hotspots
PM2	Not met	Population frequency is far above the PM2 rarity threshold of <0.1%: gnomAD v2.1 AF is 1.18898%, gnomAD v4.1 AF is 1.12825%, and gnomAD-Canada AF is 1.04812%.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in a confirmed recessive disease setting.
PM4	N/A	PM4 applies to protein length changes from in-frame insertions/deletions or stop-loss variants, and this variant is a synonymous substitution.
PM5	N/A	PM5 is a same-residue missense criterion, and this variant is synonymous; the PM5 candidate review also found no eligible classic same-residue comparator framework for use here.	pm5_candidates
PM6	Not assessed	No assumed de novo evidence was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	PP2 is a missense criterion and is not applicable to this synonymous variant.
PP3	Not met	Available computational evidence does not support a deleterious effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and missense predictors such as REVEL and BayesDel were not available for this synonymous change.	spliceai
PP4	Not assessed	No phenotype data were identified that are sufficiently specific to a disease caused by TERT variants to support PP4.
PP5	Not assessed	PP5 was not used because no independent reputable-source pathogenic assertion was identified that should be applied as stand-alone evidence.	clinvar
BA1	Met	Population frequency exceeds the benign stand-alone BA1 threshold of >1% in multiple datasets: gnomAD v2.1 AF is 1.18898%, gnomAD v4.1 AF is 1.12825%, and gnomAD-Canada AF is 1.04812%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Met	Population frequency is also above the BS1 threshold of >0.3%, with gnomAD v2.1 AF 1.18898%, gnomAD v4.1 AF 1.12825%, and gnomAD-Canada AF 1.04812%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Although this variant is seen repeatedly in population databases, the available evidence does not directly establish observation in well-phenotyped unaffected individuals in a disease context suitable for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating a normal effect of this specific variant were identified.	oncokb
BS4	Not assessed	No segregation data showing lack of cosegregation with disease were identified.
BP1	N/A	BP1 is a missense criterion and is not applicable to this synonymous variant.
BP2	Not assessed	No phase data were identified to show this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a way that would support BP2.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions without known function, and this variant is a synonymous substitution.
BP4	N/A	BP4 was not separately applied because this is a synonymous variant and the relevant computational evidence for a benign splicing effect is more appropriately captured under BP7; REVEL and BayesDel were not available for this change.	spliceai
BP5	Not assessed	No alternate molecular diagnosis or other established cause was identified to explain a phenotype independently of this variant.
BP6	Not assessed	Although ClinVar contains multiple benign submissions, there is no expert-panel review or validated reputable-source evidence here that should be used as stand-alone BP6 evidence.	clinvar
BP7	Met	This is a synonymous variant with no predicted amino acid change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, supporting no expected effect on splicing.	spliceai

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.