Starting
Initialising…
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TP53
Final classification
VUS
TP53 c.919+4A>G · p.?
TP53

NM_000546.6:c.919+4A>G is an intronic variant at the +4 position of intron 8 in TP53, evaluated under the ClinGen TP53 VCEP Specifications v2.4.0. The variant is absent from gnomAD v2.1 and v4.1, supporting PM2_Supporting.

Gene
TP53
Transcript
NM_000546.6
HGVS · transcript:coding
NM_000546.6:c.919+4A>G
Consequence
N/A
GRCh38
chr17:7673697 T>C
GRCh37
chr17:7577015 T>C
Basis Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM2 supporting (+1) + BP4 supporting (-1) = 0 points, which maps to VUS.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM2 supporting (+1) + BP4 supporting (-1) = 0 points, which maps to VUS.
Classification rationale
PM2 BP4 VUS
TP53 c.919+4A>G

NM_000546.6:c.919+4A>G is an intronic variant at the +4 position of intron 8 in TP53, evaluated under the ClinGen TP53 VCEP Specifications v2.4.0. The variant is absent from gnomAD v2.1 and v4.1, supporting PM2_Supporting.1 SpliceAI predicts no splicing impact (max delta score 0.00). As an intronic variant outside the ±1,2 canonical splice positions with SpliceAI ≤0.1, BP4_Supporting is met.2 PVS1 is not applicable as the variant lies outside the canonical ±1,2 splice donor/acceptor positions addressed by the VCEP PVS1 flowchart. PS3/BS3 functional codes are not applicable as they address missense variants and small in-frame deletions only. The variant is not located in a VCEP-specified mutational hotspot and has no amino acid change, so PM1 and PM5 are not applicable.3 With one pathogenic supporting code (PM2_Supporting, +1 point) and one benign supporting code (BP4_Supporting, -1 point), the total point value is 0. Under the Tavtigian point-based system adopted by the TP53 VCEP v2.4.0, a score of 0 falls in the range of Uncertain Significance (-1 to 5 points).4

PM2 + BP4 VUS
3 cspec ↗vcep_functional_worksheet
4 cspec ↗final_classification_framework
Gene diagram · NM_000546.6 · variants mapped to exon structure
TP53 NM_000546.6
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
      Population frequency
      Absent from gnomAD v4.1.
      Absent from gnomAD v2.1.
      This variant is absent from gnomAD-Canada.
      ClinVar screenshot
      ClinVar
      This variant is absent from ClinVar.
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
      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.
      COSMIC ↗
      Sources & reference links
      7Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC