Starting
Initialising…
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TSC2
Final classification
VUS
TSC2 c.2356-15T>A · p.?
TSC2

The TSC2 c.2356-15T>A (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where aggregate submissions include Benign, Likely benign, and Uncertain significance classifications.

Gene
TSC2
Transcript
NM_000548.5
HGVS · transcript:coding
NM_000548.5:c.2356-15T>A
Consequence
N/A
GRCh38
chr16:2074185 T>A
GRCh37
chr16:2124186 T>A
Basis Generic ACMG/AMP 2015 final-classification combination rules were used because no official ClinGen/VCEP or local custom gene-specific final-classification framework was available; the retrieved final-classification framework explicitly indicates generic ACMG fallback. ▾
Generic ACMG/AMP 2015 final-classification combination rules were used because no official ClinGen/VCEP or local custom gene-specific final-classification framework was available; the retrieved final-classification framework explicitly indicates generic ACMG fallback.
Classification rationale
PM2 BP4 VUS
TSC2 c.2356-15T>A

The TSC2 c.2356-15T>A (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where aggregate submissions include Benign, Likely benign, and Uncertain significance classifications.1 The variant is present at low frequency in population databases, with gnomAD v2.1 total AF 0.01435% (40/278790 alleles) and gnomAD v4.1 total AF 0.00571% (92/1610442 alleles), with no homozygotes reported.2 In silico splicing prediction is consistent with no significant splice effect, with SpliceAI maximal delta score 0.14.3

PM2 + BP4 → VUS
1 cosmicclinvar ↗
2 gnomad_v2 ↗gnomad_v4 ↗
3 spliceai ↗
Gene diagram · NM_000548.5 · variants mapped to exon structure
TSC2 NM_000548.5
Fetching transcript structure from UCSC…
Applied criteria · 2 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
      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= 5.71272e-05; MAF= 0.00571%, 92/1610442 alleles, homozygotes = 0) and has highest observed frequency in the HGDP:BASQUE population (AF= 0.0227273; MAF= 2.27273%, 1/44 alleles, homozygotes = 0); grpmax FAF= 0.00070689.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 0.000143477; MAF= 0.01435%, 40/278790 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000932256; MAF= 0.09323%, 33/35398 alleles, homozygotes = 0); grpmax FAF= 0.00067374.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.0057% · 92 / 1,610,442
      0 hom · FAF 0.071%
      HGDP:BASQUE
      1 / 44
      2.3%
      1KG:CLM
      1 / 188
      0.53%
      Admixed American
      57 / 60,016
      0.095%
      HGDP:XY
      1 / 1,122
      0.089%
      1KG:XX
      1 / 2,476
      0.04%
      Remaining individuals
      6 / 62,308
      0.0096%
      African/African American
      3 / 74,996
      0.004%
      European (non-Finnish)
      26 / 1,179,812
      0.0022%
      + 86 not observed (European (Finnish), Middle Eastern, South Asian, Ashkenazi Jewish, East Asian, Amish, HGDP:JAPANESE, HGDP:ADYGEI, HGDP:ORCADIAN, HGDP:BANTUSOUTHAFRICA, HGDP:YAKUT, HGDP:HAN, HGDP:UYGUR, HGDP:BALOCHI, HGDP:BEDOUIN, HGDP:RUSSIAN, HGDP:DAUR, HGDP:PIMA, HGDP:HEZHEN, HGDP:BIAKA, HGDP:MIAO, HGDP:SINDHI, HGDP:NORTHERNHAN, HGDP:OROQEN, HGDP:SAN, HGDP:TU, HGDP:TUSCAN, HGDP:MBUTI, HGDP:PALESTINIAN, HGDP:TUJIA, HGDP:DRUZE, HGDP:PATHAN, HGDP:MAKRANI, HGDP:BURUSHO, HGDP:MONGOLIAN, HGDP:BOUGAINVILLE, HGDP:PAPUANSEPIK, HGDP:YI, HGDP:NAXI, HGDP:LAHU, HGDP:SARDINIAN, HGDP:KARITIANA, HGDP:MOZABITE, HGDP:YORUBA, HGDP:DAI, HGDP:BERGAMOITALIAN, HGDP:CAMBODIAN, HGDP:FRENCH, HGDP:MANDENKA, HGDP:SURUI, HGDP:BRAHUI, HGDP:HAZARA, HGDP:KALASH, HGDP:PAPUANHIGHLANDS, HGDP:XIBO, HGDP:COLOMBIAN, HGDP:BANTUKENYA, HGDP:SHE, HGDP:MAYA, HGDP:XX, 1KG:ESN, 1KG:PUR, 1KG:PJL, 1KG:JPT, 1KG:CHB, 1KG:STU, 1KG:ITU, 1KG:TSI, 1KG:MXL, 1KG:CEU, 1KG:MSL, 1KG:BEB, 1KG:YRI, 1KG:FIN, 1KG:KHV, 1KG:CDX, 1KG:LWK, 1KG:ACB, 1KG:ASW, 1KG:IBS, 1KG:GBR, 1KG:PEL, 1KG:GIH, 1KG:CHS, 1KG:GWD, 1KG:XY)
      gnomAD v2.1
      0.014% · 40 / 278,790
      0 hom · FAF 0.067%
      Admixed American
      33 / 35,398
      0.093%
      Remaining individuals
      3 / 7,172
      0.042%
      European (non-Finnish)
      4 / 126,084
      0.0032%
      + 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
      gnomAD v4 ↗ gnomAD v2 ↗
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory).
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).
      SpliceAI ↗
      Functional No data
      No calibrated functional assay or RNA evidence was identified for this variant.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Somatic evidence
      COSMIC
      This variant has not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant cancer hotspot.
      Sources & reference links
      5Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB