Starting
Initialising…
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PTEN
Final classification
Likely Pathogenic
PTEN c.743del · p.Pro248LeufsTer8
PTEN

The PTEN c.743del (p.(Pro248LeufsTer8)) variant has been observed in somatic cancers in COSMIC (COSV109436597, n=2) and has been reported in ClinVar as pathogenic.

Gene
PTEN
Transcript
NM_000314.8
HGVS · transcript:coding
NM_000314.8:c.743del
Consequence
N/A
GRCh38
chr10:87957959 AC>A
GRCh37
chr10:89717716 AC>A
Basis Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework; Rule20 applies.
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework; Rule20 applies.
Classification rationale
PVS1PM2 Likely Pathogenic
PTEN c.743del

The PTEN c.743del (p.(Pro248LeufsTer8)) variant has been observed in somatic cancers in COSMIC (COSV109436597, n=2) and has been reported in ClinVar as pathogenic.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2_Supporting threshold of 0.001% and supports rarity in the general population.2 The variant is a frameshift predicted to truncate PTEN at codon 255, and under the PTEN Expert Panel PVS1 decision tree this position is 5' of the p.D375 threshold for full-strength PVS1 in transcript NM_000314.8.3 SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.06), and this does not alter the interpretation of the variant as a loss-of-function frameshift.4

PVS1 + PM2 Likely Pathogenic
3 cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
Gene diagram · NM_000314.8 · variants mapped to exon structure
PTEN NM_000314.8
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 · supports pathogenic
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      Absent from gnomAD v4.1.
      v2.1
      Absent from gnomAD v2.1.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD v2.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories).
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
      Functional / OncoKB screenshot
      Functional Likely Oncogenic
      OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
      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; COSV109436597, n = 2 times).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      Sources & reference links
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots