Starting
Initialising…
0%
PTEN
Final classification
VUS
PTEN c.165-7T>C · p.?
PTEN

NM_000314.8:c.165-7T>C is an intronic variant in PTEN located at position -7 of the intron 2 splice acceptor region.

Gene
PTEN
Transcript
NM_000314.8
HGVS · transcript:coding
NM_000314.8:c.165-7T>C
Consequence
N/A
GRCh38
chr10:87925506 T>C
GRCh37
chr10:89685263 T>C
Basis Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BS1 strong benign; no rule matched the adjudicated criteria.
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BS1 strong benign; no rule matched the adjudicated criteria.
Classification rationale
BS1 VUS
PTEN c.165-7T>C

NM_000314.8:c.165-7T>C is an intronic variant in PTEN located at position -7 of the intron 2 splice acceptor region. This variant is present in gnomAD v4.1 at a grpmax filtering allele frequency of 0.006% (11/1,587,106 alleles), which falls within the PTEN VCEP BS1_Strong range (0.0043%-0.056%), indicating the variant is observed at a population frequency greater than expected for a highly penetrant autosomal dominant disorder.1 The variant is classified as Likely benign in ClinVar (VCV000412808) by 5 clinical laboratories, consistent with the population frequency evidence.2 SpliceAI predicts no significant splicing impact (max delta score = 0.02), which falls within the benign range for computational splice prediction but is not sufficient alone to apply BP4 under the PTEN VCEP without VarSeak concordance.3 No pathogenic computational predictions, functional assay data, segregation evidence, de novo observations, or case-level phenotype data were identified to support pathogenicity for this variant. The variant does not meet PM2 under PTEN VCEP rules because the South Asian subpopulation frequency (0.0111%) exceeds the VCEP subpopulation threshold of 0.002%.4

BS1 VUS
Gene diagram · NM_000314.8 · variants mapped to exon structure
PTEN NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 1 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= 6.93085e-06; MAF= 0.00069%, 11/1587106 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000110978; MAF= 0.01110%, 10/90108 alleles, homozygotes = 0); grpmax FAF= 5.997e-05.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 4.2304e-06; MAF= 0.00042%, 1/236384 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.34986e-05; MAF= 0.00335%, 1/29852 alleles, homozygotes = 0).
      🇨🇦 CA
      This variant is absent from gnomAD-Canada.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.00069% · 11 / 1,587,106
      0 hom · FAF 0.006%
      South Asian
      10 / 90,108
      0.011%
      Remaining individuals
      1 / 61,718
      0.0016%
      + 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
      gnomAD v2.1
      0.00042% · 1 / 236,384
      0 hom
      South Asian
      1 / 29,852
      0.0033%
      + 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Likely benign (5 clinical laboratories). (ClinVarID = 412808)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
      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
      Triaged references · 9 PMIDs not cited in assessment
      25645574 ↗ ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. CLINVAR
      25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR
      15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR
      17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR
      20301661 ↗ PTEN Hamartoma Tumor Syndrome. CLINVAR
      23519317 ↗ Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. CLINVAR
      23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR
      24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR