LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-02
Case ID: NM_198253.2_c.2775C_T_20260802_162853
Framework: ACMG/AMP 2015
Variant classification summary

NM_198253.2:c.2775C>T

TERT  · NP_937983.2:p.(His925=)  · NM_198253.2
GRCh37: chr5:1264587 G>A  ·  GRCh38: chr5:1264472 G>A
Gene: TERT Transcript: NM_198253.2
Final call
Likely Benign
BP6 supporting benign BP7 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
TERT
Transcript
NM_198253.2
Protein
NP_937983.2:p.(His925=)
gnomAD AF
0.000748516907931181 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_198253.2:c.2775C>T is a synonymous variant (p.His925=) in exon 11 of TERT. SpliceAI predicts no splicing impact (delta score = 0.00).
2
This variant is present in gnomAD v4.1 at a global allele frequency of 0.075% (1208/1,613,858 alleles) with 12 homozygotes observed, and is common in the Ashkenazi Jewish subpopulation (~2%).
3
ClinVar classifies this variant as Likely benign by 9 clinical laboratories and Benign by 5 clinical laboratories (Variation ID 242230), representing a strong consensus of benign interpretation across 14 independent clinical testing laboratories.
4
No publication was found that mentions this specific variant (NM_198253.2:c.2775C>T). The TERT functional study by Yamaguchi et al. (PMID:15814878) examined only nonsynonymous mutations at codons 202, 412, 694, 772, and 1090. The ACMG/AMP guidelines paper (PMID:25741868) does not discuss individual variants. GeneReviews and PDQ summaries (PMIDs:20301408, 20301779, 26389258, 26389333) provide general gene-level overviews without variant-specific data.
5
Two supporting benign criteria are met: BP6 (ClinVar consensus of benign classification by multiple clinical laboratories) and BP7 (synonymous variant with no predicted splice impact, and the nucleotide is not conserved as evidenced by high population frequency with multiple homozygotes). Under ACMG/AMP 2015 combination rules, ≥2 supporting benign criteria yields a classification of 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 Synonymous variant (p.His925=) produces no null effect on the protein; does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical splice site).
pvs1_generic_framework
PS1 N/A Synonymous variant produces no amino acid change; there is no same-amino-acid-change comparator possible.
PS2 Not met No de novo data available for this variant.
PS3 Not met No functional data exists for this synonymous variant. The published TERT functional studies (PMID:15814878) examined nonsynonymous mutations at codons 202, 412, 694, 772, and 1090, not residue 925.
PMID:15814878
PS4 Not met No case-control data or statistically significant enrichment of this variant in affected individuals versus controls.
PS5 Not met No experimental evidence that this synonymous variant affects gene function through an established functional assay.
PM1 Not met This synonymous variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org negative), and position 925 is not within a characterized critical functional domain that a synonymous change would disrupt.
PM2 Not met Global allele frequency in gnomAD v4.1 is 0.075% (1208/1,613,858 alleles), approaching the 0.1% PM2 threshold. The variant is common in the Ashkenazi Jewish subpopulation (~2%) with 12 homozygotes observed, which is inconsistent with a rare pathogenic variant.
gnomad_v2 gnomad_v4
PM5 N/A Synonymous variant produces no amino acid change; unable to assess same-residue alternate missense comparator.
PM6 Not met No de novo observation reported for this variant.
PP1 Not met No segregation data available for this variant.
PP2 N/A PP2 applies to missense variants in genes with low rate of benign missense variation. This is a synonymous variant.
PP3 Not met SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL, BayesDel, and HCI Prior scores are unavailable for this synonymous variant. No in silico evidence supports a damaging effect.
spliceai
PP4 Not met No patient phenotype or family history data available to assess specificity for a TERT-related disorder.
PP5 Not met ClinVar classifies this variant as Likely benign/Benign (Variation ID 242230), not pathogenic. No expert panel has reported it as pathogenic. The ClinVar review status is 'criteria provided, single submitter' (1-star), not the 3-star expert panel threshold.
clinvar
BA1 Not met Global allele frequency in gnomAD is below 1% (v2.1: 0.105%, v4.1: 0.075%). The Ashkenazi Jewish subpopulation frequency of ~2% does not satisfy BA1 under global population conventions.
gnomad_v2 gnomad_v4
BS1 Not met Global allele frequency in gnomAD is below 0.3% (v2.1: 0.105%, v4.1: 0.075%). Does not meet the >0.3% BS1 threshold.
gnomad_v2 gnomad_v4
BS2 Not met No specific observation of this variant in healthy adults documented with expected full-penetrance early-age phenotype absent.
BS3 Not met No functional studies have been performed on this variant to demonstrate no damaging effect on protein function or splicing.
BS4 Not met No segregation data available to demonstrate lack of cosegregation with disease.
BP1 N/A BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is a synonymous variant.
BP2 Not met No evidence that this variant has been observed in trans with a pathogenic variant in a recessive disorder.
BP4 Not met Insufficient multiple lines of computational evidence. Only SpliceAI is available (delta=0.00); REVEL, BayesDel, and conservation scores are not applicable or unavailable for this synonymous variant.
spliceai
BP5 Not met No observation of this variant in a case where an alternate molecular basis for disease was identified.
BP6 Met ClinVar reports this variant as Likely benign by 9 clinical laboratories and Benign by 5 clinical laboratories (Variation ID 242230). Fourteen independent clinical laboratory submissions converge on a benign interpretation. Review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel, but the volume and consistency of benign classifications from multiple clinical testing laboratories supports a benign interpretation under generic ACMG.
clinvar
BP7 Met Synonymous variant (p.His925=) with SpliceAI predicting no splice impact (max delta score = 0.00). The high population frequency (up to 2% in Ashkenazi Jewish, with 12 homozygotes in gnomAD v4.1) suggests the nucleotide is not highly conserved. A silent variant with no predicted splicing effect and no conservation constraint meets BP7.
spliceai gnomad_v2 gnomad_v4
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