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PTEN
Final classification
Benign
PTEN c.-666G>A · p.?
PTEN

NM_000314.8:c.-666G>A exceeds the PTEN VCEP BA1 allele frequency threshold with a gnomAD filtering allele frequency of 0.1076% (v2.1) and 0.1864% (v4.1), both above the 0.056% stand-alone benign cutoff. One homozygote is observed in gnomAD v4.1, inconsistent with an autosomal dominant high-penetrance disorder.

Gene
PTEN
Transcript
NM_000314.8
HGVS · transcript:coding
NM_000314.8:c.-666G>A
Consequence
N/A
GRCh38
chr10:87863804 G>A
GRCh37
chr10:89623561 G>A
Basis Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign; maps to Benign. ▾
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign; maps to Benign.
Classification rationale
BA1 Benign
PTEN c.-666G>A

NM_000314.8:c.-666G>A exceeds the PTEN VCEP BA1 allele frequency threshold with a gnomAD filtering allele frequency of 0.1076% (v2.1) and 0.1864% (v4.1), both above the 0.056% stand-alone benign cutoff. One homozygote is observed in gnomAD v4.1, inconsistent with an autosomal dominant high-penetrance disorder.1 This is an upstream 5' UTR variant (c.-666G>A) with no predicted splicing impact (SpliceAI max delta = 0.04). Multiple benign-frequency observations and a homozygote in population databases support a benign interpretation.2

BA1 → Benign
1 gnomad_v2 ↗gnomad_v4 ↗cspec ↗
2 spliceai ↗gnomad_v2 ↗gnomad_v4 ↗
Gene diagram · NM_000314.8 · variants mapped to exon structure
PTEN NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 14 assessed
Applied · 1
Strength Supporting Moderate Strong Very strong
✓
BA1 stand-alone Benign
NM_000314.8:c.-666G>A exceeds the PTEN VCEP BA1 allele frequency threshold. The gnomAD filtering allele frequency (grpmax FAF) is 0.001076 (0.1076%) in v2.1 and 0.001864 (0.1864%) in v4.1, both well above the 0.00056 (0.056%) stand-alone benign threshold. Additionally, one homozygote is observed in gnomAD v4.1 (African/African American population, genome data), which is inconsistent with an autosomal dominant highly penetrant disorder.
gnomAD v2.1 grpmax FAF = 0.001076 (0.1076%) > VCEP BA1 threshold 0.00056 (0.056%)gnomAD v4.1 grpmax FAF = 0.001864 (0.1864%) > VCEP BA1 threshold 0.00056 (0.056%)gnomAD v4.1: 1 homozygote in African/African American population (genome data)
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
Assessed · not applied
Pathogenic
PS2 No de novo observation data available for NM_000314.8:c.-666G>A.
PS3 No functional data available for NM_000314.8:c.-666G>A.
PS4 No proband specificity score data available for NM_000314.8:c.-666G>A.
PM2 NM_000314.8:c.-666G>A is present in gnomAD at frequencies well above the PTEN VCEP PM2_Supporting threshold of <0.001% (0.00001).
PM6 No de novo observation data available for NM_000314.8:c.-666G>A.
PP1 No co-segregation data available for NM_000314.8:c.-666G>A.
PP3 Multiple lines of computational evidence do not support a deleterious effect.
Benign
BS1 The gnomAD filtering allele frequency for NM_000314.8:c.-666G>A (0.1076% v2.1, 0.1864% v4.1) exceeds the PTEN VCEP BS1 upper bound of 0.056%.
BS2 One homozygote is observed in gnomAD v4.1 (genome data, African/African American population), but the clinical phenotype of this individual is unknown.
BS3 No functional studies demonstrating no damaging effect are available for NM_000314.8:c.-666G>A.
BS4 No segregation data available for NM_000314.8:c.-666G>A.
BP2 No data available regarding NM_000314.8:c.-666G>A observed in trans with a pathogenic PTEN variant or in cis with multiple pathogenic PTEN variants.
BP4 NM_000314.8:c.-666G>A is an upstream 5' UTR variant.
BP5 No data available indicating NM_000314.8:c.-666G>A was found in a case with an alternate molecular basis for disease.
N/A · 11 PVS1 · PS1 · PM1 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · BP6 · BP7
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= 0.000281764; MAF= 0.02818%, 109/386848 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00220503; MAF= 0.22050%, 106/48072 alleles, homozygotes = 1); grpmax FAF= 0.0018642.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000486981; MAF= 0.04870%, 15/30802 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00174703; MAF= 0.17470%, 15/8586 alleles, homozygotes = 0); grpmax FAF= 0.00107604.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010901558922925978, 2/18346 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.028% · 109 / 386,848
1 hom · FAF 0.19%
African/African American
106 / 48,072
0.22%
1 hom
Admixed American
3 / 22,210
0.014%
+ 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
0.049% · 15 / 30,802
0 hom · FAF 0.11%
African/African American
15 / 8,586
0.17%
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
0.011% · 2 / 18,346
0 hom · FAF 0.035%
African/African American
2 / 1,014
0.2%
+ 8 not observed (Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals, South Asian)
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is present in ClinVar (Variation ID: 189528); submission details unavailable.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
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.
COSMIC ↗
Sources & reference links
8Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Triaged references · 6 PMIDs not cited in assessment
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
17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR
20301661 ↗ PTEN Hamartoma Tumor Syndrome. CLINVAR
24071797 ↗ Recommendations from the EGAPP Working Group: does PCA3 testing for the diagnosis and management of prostate cancer improve patient health outcomes? CLINVAR
24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR
26389210 ↗ Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version. CLINVAR