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TERT
Final classification
Benign
TERT c.835G>A · p.Ala279Thr
TERT

The TERT c.835G>A (p.Ala279Thr, p.A279T) variant has been reported in ClinVar as benign by 18 clinical laboratories.

Gene
TERT
Transcript
NM_198253.2
HGVS · transcript:coding
NM_198253.2:c.835G>A
Consequence
N/A
GRCh38
chr5:1294051 C>T
GRCh37
chr5:1294166 C>T
Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP4 supporting benign; combination = 1 stand-alone benign, which maps to Benign. ▾
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP4 supporting benign; combination = 1 stand-alone benign, which maps to Benign.
Classification rationale
BA1BS1BP4 Benign
TERT c.835G>A

The TERT c.835G>A (p.Ala279Thr, p.A279T) variant has been reported in ClinVar as benign by 18 clinical laboratories.1 This variant is common in population databases, with a total allele frequency of 2.314% in gnomAD v2.1 and 2.712% in gnomAD v4.1; the highest observed population frequency is 5.889% in Finnish individuals in v2.1 and 5.675% in Finnish individuals in v4.1.2 In silico results do not support a damaging effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.162, and BayesDel is -0.293678.3

BA1 + BS1 + BP4 → Benign
1 clinvar ↗
2 gnomad_v2 ↗gnomad_v4 ↗
3 spliceai ↗revelbayesdel
Gene diagram · NM_198253.2 · variants mapped to exon structure
TERT NM_198253.2
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      —
      Research & evidence
      Population frequency · supports benign
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      This variant is present in gnomAD v4.1 (AF= 0.0271163; MAF= 2.71163%, 43173/1592140 alleles, homozygotes = 703) and has highest observed frequency in the European (Finnish) population (AF= 0.0567474; MAF= 5.67474%, 3317/58452 alleles, homozygotes = 99); grpmax FAF= 0.0298216.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 0.0231414; MAF= 2.31414%, 5568/240608 alleles, homozygotes = 100) and has highest observed frequency in the European (Finnish) population (AF= 0.0588917; MAF= 5.88917%, 1118/18984 alleles, homozygotes = 30); grpmax FAF= 0.0337522.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      2.7% · 43173 / 1,592,140
      703 hom · FAF 3%
      European (Finnish)
      3317 / 58,452
      5.7%
      99 hom
      European (non-Finnish)
      35244 / 1,171,484
      3%
      536 hom
      Ashkenazi Jewish
      869 / 29,254
      3%
      16 hom
      Remaining individuals
      1487 / 61,652
      2.4%
      21 hom
      South Asian
      1223 / 88,730
      1.4%
      24 hom
      Admixed American
      623 / 57,978
      1.1%
      5 hom
      Middle Eastern
      58 / 6,036
      0.96%
      1 hom
      African/African American
      345 / 74,420
      0.46%
      1 hom
      Amish
      4 / 912
      0.44%
      East Asian
      3 / 43,222
      0.0069%
      gnomAD v2.1
      2.3% · 5568 / 240,608
      100 hom · FAF 3.4%
      European (Finnish)
      1118 / 18,984
      5.9%
      30 hom
      European (non-Finnish)
      3208 / 106,710
      3%
      46 hom
      Ashkenazi Jewish
      286 / 9,610
      3%
      5 hom
      Remaining individuals
      169 / 6,458
      2.6%
      8 hom
      South Asian
      348 / 27,822
      1.3%
      10 hom
      Admixed American
      337 / 32,630
      1%
      1 hom
      African/African American
      99 / 21,242
      0.47%
      East Asian
      3 / 17,152
      0.017%
      gnomAD v4 ↗ gnomAD v2 ↗
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Benign (18 clinical laboratories). (ClinVarID = 39125)
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.162. BayesDel score = -0.293678.
      SpliceAI ↗
      Functional / OncoKB screenshot
      Functional Unknown Oncogenic Effect
      OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TERT is an enzyme that functions to maintain telomere length and genomic stability. The TERT promoter is frequently mutated in various cancer types.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      Cancer hotspots
      Somatic evidence Not in COSMIC / hotspots
      COSMIC
      This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57209966, n = 11 times).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      COSMIC ↗ Hotspots ↗
      Sources & reference links
      7Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots