NM_198253.2:c.2781A>G

TERT · NP_937983.2:p.(Leu927=) · NM_198253.2

GRCh37: chr5:1264581 T>C · GRCh38: chr5:1264466 T>C

Gene: TERT Transcript: NM_198253.2

Final call

VUS

PM2 supporting BP7 supporting benign

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(Leu927=)

gnomAD AF

1.4872450149406155e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_198253.2:c.2781A>G (p.Leu927=) in TERT is a synonymous variant with extremely low population frequency (gnomAD v4.1 AF = 0.00149%, 24/1,613,722 alleles; absent from gnomAD v2.1), meeting PM2 at supporting strength.

SpliceAI predicts no splicing alteration (max delta = 0.00), consistent with a silent variant, meeting BP7 at supporting_benign strength.

PVS1 is not met as this synonymous variant does not qualify as a null variant per the ClinGen SVI PVS1 decision framework (PMC6185798). Computational evidence is insufficient for PP3 or BP4. No variant-specific functional studies, case-control data, segregation data, or de novo observations are available. ClinVar reports mixed classifications (Uncertain significance, Likely benign, Benign) from single submitters without expert panel consensus.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP7), the net evidence weight is indeterminate. This variant is classified as a Variant of Uncertain Significance.

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	Not met	NM_198253.2:c.2781A>G is a synonymous variant (p.Leu927=) that does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework
PS1	N/A	Synonymous variant with no amino acid change; PS1 requires a different nucleotide change producing the same amino acid change as an established pathogenic variant.
PS2	Not assessed	No de novo observation with confirmed paternity and maternity has been reported for this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies supporting a damaging effect have been identified for this specific synonymous variant.
PS4	Not met	No case-control data demonstrate significantly increased prevalence of this variant in affected individuals. ClinVar-associated PMIDs (20301408, 20301779, 26389258, 26389333) are GeneReviews/PDQ summaries that do not mention this specific variant.	clinvar
PS5	Not met	No reputable source has recently reported this variant as pathogenic. ClinVar aggregate classification is Uncertain significance with mixed submissions (2 US, 2 LB, 1 B); no expert panel consensus exists.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot per hotspot analysis, and no critical functional domain has been specifically implicated at codon 927.
PM2	Met	This variant is extremely rare in population databases, with an allele frequency of 0.00149% (24/1,613,722 alleles) in gnomAD v4.1 and absent from gnomAD v2.1, well below the 0.1% PM2 threshold.	gnomad_v4 gnomad_v2
PM5	N/A	Synonymous variant with no amino acid change; cannot evaluate same-residue pathogenic missense comparator per PM5 semantics.
PM6	Not assessed	No de novo observation (with or without confirmed paternity) has been reported for this variant.
PP1	Not assessed	No co-segregation data with disease in multiple affected family members has been reported for this variant.
PP2	N/A	PP2 is specific to missense variants in genes with a low rate of benign missense variation. NM_198253.2:c.2781A>G is a synonymous (silent) variant, not a missense change.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). REVEL, BayesDel, and HCI prior scores are unavailable for this variant.	spliceai
PP4	Not assessed	No patient phenotype or family history data are available to determine whether the clinical presentation is highly specific for a TERT-associated disorder.
PP5	Not met	Of the four ClinVar-associated PMIDs flagged as PP5 candidates (GeneReviews/PDQ summaries: 20301408, 20301779, 26389258, 26389333), none mention NM_198253.2:c.2781A>G. These are gene-level reviews of TERT-associated disorders and do not constitute variant-specific evidence.	clinvar
BA1	Not met	The population allele frequency of 0.00149% in gnomAD v4.1 is far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	The population allele frequency of 0.00149% in gnomAD v4.1 is far below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not met	No homozygotes have been observed in gnomAD v4.1 (24 heterozygous alleles among 1,613,722 total alleles), failing to meet the requirement for observation in a healthy adult homozygous state.	gnomad_v4
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect have been identified for this specific synonymous variant.
BS4	Not assessed	No family segregation data are available to evaluate lack of segregation with disease.
BP1	N/A	BP1 is specific to missense variants in genes where truncating variants are the primary disease mechanism. NM_198253.2:c.2781A>G is a synonymous variant, not a missense change.
BP2	Not assessed	No data on observation in trans with a dominant pathogenic variant are available.
BP4	Not met	Insufficient computational evidence to meet the 'multiple lines' threshold. SpliceAI predicts no splicing impact (delta = 0.00), but REVEL, BayesDel, and nucleotide conservation scores are unavailable for this variant.	spliceai
BP5	Not assessed	No data on observation in a case with an alternate molecular basis for disease are available.
BP6	Not met	ClinVar contains one benign and two likely benign single-submitter classifications, but these lack expert panel review or a published assertion from a reputable source with unavailable supporting evidence.	clinvar
BP7	Met	NM_198253.2:c.2781A>G is a synonymous variant (p.Leu927=). SpliceAI predicts no impact on splicing with a maximum delta score of 0.00, consistent with a silent variant unlikely to alter gene product or splicing.	spliceai
BP3	N/A	Skipped per directive; this variant is a substitution, not an in-frame indel in a repetitive region.
PM3	N/A	Skipped per directive; TERT-associated disorders follow autosomal dominant or autosomal recessive inheritance patterns requiring specific trans/phase data not available for this assessment.
PM4	N/A	Skipped per directive; this variant is a single-nucleotide substitution, not a protein-length-altering change.

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