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PTENc.-666G>ABenign
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Variant interpretation report

PTEN c.-666G>A, p.?

NM_000314.8:c.-666G>A NP_000305.3:p.? View identifiers
Classification
Benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.

Benign.A benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PTEN

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen PTEN VCEP v3.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 1
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 1
BA1Stand alone
BA1 · stand alone

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.

Recorded classification: 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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
109 / 386,848 alleles

gnomAD v4.1: 109 / 386,848 alleles. Recorded AF 0.000281764. Recorded homozygote count 1.

gnomAD 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.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00010901558922925978, 2/18346 alleles, homozygotes = 0).

Applied · BA1 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.040 maximum delta

Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen PTEN VCEP v3.2.0, with the data and sources behind each one.

27 criteria with recorded statuses: 1 met · 14 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

Met · 1

BA1 Stand aloneNM_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. Details ▾Hide ▴
Evidence considered
  • 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)
  • PTEN VCEP BA1: gnomAD Filtering allele frequency >0.00056 (0.056%)
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗

Not met · 14 · evaluated, threshold not reached

PS2 No de novo observation data available for NM_000314.8:c.-666G>A. Neither proven nor assumed de novo events have been reported. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in ClinVar
  • literature
  • or evidence brief.
Still missing
  • No de novo testing or family studies available.
PS3 No functional data available for NM_000314.8:c.-666G>A. The PTEN VCEP PS3 functional assay (Mighell et al. 2018, mmc2.xlsx) covers missense variants only via phosphatase activity assay; this upstream variant is not represented. No splicing assay data available. Details ▾Hide ▴
Evidence considered
  • PTEN mmc2.xlsx functional assay (PMID:29706350) is limited to missense variants
  • c.-666G>A is upstream non-coding.
Still missing
  • No functional data for upstream non-coding variants in PTEN.
Sources
vcep_mmc2
PS4 No proband specificity score data available for NM_000314.8:c.-666G>A. The PTEN VCEP PS4 requires enumeration of probands with phenotype specificity scoring; no such data were identified. Details ▾Hide ▴
Evidence considered
  • No proband counts or phenotype specificity data available.
Still missing
  • No case-level phenotype data with PTEN specificity scoring.
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). gnomAD v2.1 overall AF = 0.0487% (15/30,802 alleles); gnomAD v4.1 overall AF = 0.0282% (109/386,848 alleles). The African/African American subpopulation AF is 0.1747% in v2.1 and 0.2205% in v4.1, far exceeding the subpopulation threshold of 0.002%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF=0.000487 (0.0487%)
  • 15/30802 alleles
  • 0 homozygotes
  • gnomAD v4.1: AF=0.000282 (0.0282%)
  • 109/386848 alleles
  • 1 homozygote
  • gnomAD v2.1 African subpopulation: AF=0.001747 (0.1747%)
  • 15/8586 alleles
  • gnomAD v4.1 African subpopulation: AF=0.002205 (0.2205%)
  • 106/48072 alleles
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM6 No de novo observation data available for NM_000314.8:c.-666G>A. No assumed or confirmed de novo events have been reported. Details ▾Hide ▴
Evidence considered
  • No de novo data identified.
Still missing
  • No de novo testing or family studies available.
PP1 No co-segregation data available for NM_000314.8:c.-666G>A. No family studies with meiotic counts have been reported. Details ▾Hide ▴
Evidence considered
  • No segregation data identified.
Still missing
  • No family co-segregation studies available.
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI max delta score = 0.04, indicating no predicted splicing impact. REVEL and BayesDel scores are not available (non-coding variant). The PTEN VCEP PP3 threshold (REVEL >0.7 for missense; SpliceAI + VarSeak concordance for splicing) is not met. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.04 (no predicted splice impact)
  • REVEL not available (non-coding variant)
  • BayesDel not available (non-coding variant)
Sources
spliceai ↗cspec ↗
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%. The variant is captured by BA1 at the stand-alone benign level; BS1 is superseded. Details ▾Hide ▴
Evidence considered
  • gnomAD grpmax FAF exceeds BS1 range (0.0043%-0.056%)
  • BA1 threshold met instead.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS2 One homozygote is observed in gnomAD v4.1 (genome data, African/African American population), but the clinical phenotype of this individual is unknown. The PTEN VCEP BS2 requires observation in a healthy or PHTS-unaffected individual; gnomAD population data alone do not confirm unaffected status. Additionally, BS2 would be downgraded to supporting if BS1 were also applied. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 1 homozygote (genome
  • African/African American)
  • phenotype unknown
  • VCEP BS2 requires confirmed healthy or PHTS-unaffected status
Still missing
  • Phenotype of the gnomAD homozygote is unknown
  • cannot confirm unaffected status.
Sources
gnomad_v4 ↗
BS3 No functional studies demonstrating no damaging effect are available for NM_000314.8:c.-666G>A. The PTEN VCEP BS3_Strong requires an RNA/mini-gene splicing assay demonstrating no impact. The VCEP BS3_Supporting (phosphatase activity >0 per Mighell et al. 2018) applies only to missense variants. SpliceAI max delta of 0.04 is consistent with no splicing impact but does not substitute for a direct functional assay. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.04 (no predicted splice impact)
  • but VCEP BS3_Strong requires direct assay
  • PTEN mmc2.xlsx functional data limited to missense variants
Still missing
  • No direct RNA or mini-gene splicing assay data for this variant.
Sources
spliceai ↗vcep_mmc2cspec ↗
BS4 No segregation data available for NM_000314.8:c.-666G>A. The PTEN VCEP BS4 requires lack of segregation in affected family members; no family studies have been reported. Details ▾Hide ▴
Evidence considered
  • No segregation data identified.
Still missing
  • No family segregation studies available.
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. Details ▾Hide ▴
Evidence considered
  • No trans/cis phase data identified.
Still missing
  • No phase data with other PTEN variants.
BP4 NM_000314.8:c.-666G>A is an upstream 5' UTR variant. The PTEN VCEP BP4 specification applies to synonymous or intronic variants with concordant SpliceAI (0-0.2) and VarSeak (Class 1-2) benign predictions. While SpliceAI max delta is 0.04 (no predicted splice impact), the variant is not synonymous or intronic per the VCEP scope, and VarSeak data are not available. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.04 (consistent with no splicing impact)
  • VCEP BP4 is specified for synonymous or intronic variants
  • upstream variant does not match
Still missing
  • VarSeak data not available
  • variant type outside VCEP BP4 scope.
Sources
spliceai ↗cspec ↗
BP5 No data available indicating NM_000314.8:c.-666G>A was found in a case with an alternate molecular basis for disease. The PTEN VCEP BP5 requires a variant found in a case with an alternate highly penetrant molecular diagnosis where phenotypes do not overlap. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis data identified.
Still missing
  • No data on cases with alternate molecular diagnoses.
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000314.8:c.-666G>A is an upstream 5' UTR variant, not a null variant (nonsense, frameshift, or canonical splice site). The PTEN PVS1 decision tree does not apply to non-null variants. Details ▾Hide ▴
Evidence considered
  • Upstream variant c.-666G>A
  • variant_bucket='other'
  • not a null variant eligible for PVS1 decision tree.
Sources
pvs1_variant_assessmentvcep_pvs1_decisiontree_pten
PS1 N/ANM_000314.8:c.-666G>A is an upstream non-coding variant that does not alter the amino acid sequence. PS1 requires the same amino acid change as a known pathogenic variant. Details ▾Hide ▴
Evidence considered
  • Upstream variant
  • no protein change (NP_000305.3:p.?)
PM1 N/ANM_000314.8:c.-666G>A is an upstream non-coding variant and does not reside in any of the PTEN catalytic motif residues (NP_000305.3: 90-94, 123-130, 166-168) as defined by the PTEN VCEP PM1 specification. Details ▾Hide ▴
Evidence considered
  • Upstream variant c.-666
  • not within coding region
  • let alone catalytic motifs.
Sources
cspec ↗
PM5 N/ANM_000314.8:c.-666G>A is an upstream non-coding variant, not a missense change. PM5 requires a missense change at an amino acid residue where a different pathogenic missense has been observed. Details ▾Hide ▴
Evidence considered
  • Upstream variant
  • no amino acid residue context
  • pm5_candidates confirms not_applicable.
Sources
pm5_candidates
PP2 N/ANM_000314.8:c.-666G>A is an upstream non-coding variant, not a missense variant. PP2 applies to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
  • Upstream variant
  • PP2 is missense-specific.
Sources
cspec ↗
PP4 VCEPPTEN VCEP specifies PP4 as Not Applicable. Phenotype specificity has been incorporated into PS4 rule specifications. Details ▾Hide ▴
Evidence considered
  • VCEP PP4 applicability: Not Applicable.
Sources
cspec ↗
PP5 VCEPPTEN VCEP specifies PP5 as Not Applicable. Details ▾Hide ▴
Evidence considered
  • VCEP PP5 applicability: Not Applicable.
Sources
cspec ↗
BP1 VCEPPTEN VCEP specifies BP1 as Not Applicable. Details ▾Hide ▴
Evidence considered
  • VCEP BP1 applicability: Not Applicable.
Sources
cspec ↗
BP3 VCEPSkipped per instructions. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPPTEN VCEP specifies BP6 as Not Applicable. Details ▾Hide ▴
Evidence considered
  • VCEP BP6 applicability: Not Applicable.
Sources
cspec ↗
BP7 N/ANM_000314.8:c.-666G>A is an upstream 5' UTR variant (c.-666). The PTEN VCEP BP7 applies to synonymous or intronic variants at or beyond +7/-21 splice positions. This upstream variant is outside the BP7 scope. Details ▾Hide ▴
Evidence considered
  • Upstream variant c.-666
  • VCEP BP7 is for synonymous/intronic variants near splice sites.
Sources
cspec ↗
PS5 N/APS5 is not a recognized ACMG/AMP criterion code. No assessment applicable. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.-666G>A
Protein (HGVS p.)
NP_000305.3:p.?
GRCh38
chr10:87863804 G>A
GRCh37
chr10:89623561 G>A
ClinVar
189528

Gene diagram

Every interpreted variant in PTEN, mapped onto the exon structure of NM_000314.8. Select a row to find it on the plot.

PTENNM_000314.8
Fetching transcript structure from UCSC…
gnomAD v4.1 109 / 386,848 alleles AF 0.000282 · 1 homozygotes · FAF 0.00186
gnomAD v2.1 15 / 30,802 alleles AF 0.000487 · 0 homozygotes · FAF 0.00108
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00028 · 109 / 386,848 alleles · 1 hom · FAF 0.0019
African/African American106 / 48,072 0.00221 hom
Admixed American3 / 22,210 0.00014
0 alternate alleles recorded in 8 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).

gnomAD v2.1

AF 0.00049 · 15 / 30,802 alleles · 0 hom · FAF 0.0011
African/African American15 / 8,586 0.0017
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD 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.

gnomAD 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.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00010901558922925978, 2/18346 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -161 bp
0.000
SpliceAI acceptor gainat +235 bp
0.000
SpliceAI donor lossat -51 bp
0.040
SpliceAI donor gainat +80 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI max delta score = 0.04, indicating no predicted splicing impact. REVEL and BayesDel scores are not available (non-coding variant). The PTEN VCEP PP3 threshold (REVEL >0.7 for missense; SpliceAI + VarSeak concordance for splicing) is not met. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.04 (no predicted splice impact)
  • REVEL not available (non-coding variant)
  • BayesDel not available (non-coding variant)
Sources
spliceai ↗cspec ↗
BP4 NM_000314.8:c.-666G>A is an upstream 5' UTR variant. The PTEN VCEP BP4 specification applies to synonymous or intronic variants with concordant SpliceAI (0-0.2) and VarSeak (Class 1-2) benign predictions. While SpliceAI max delta is 0.04 (no predicted splice impact), the variant is not synonymous or intronic per the VCEP scope, and VarSeak data are not available. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.04 (consistent with no splicing impact)
  • VCEP BP4 is specified for synonymous or intronic variants
  • upstream variant does not match
Still missing
  • VarSeak data not available
  • variant type outside VCEP BP4 scope.
Sources
spliceai ↗cspec ↗
BP7 N/ANM_000314.8:c.-666G>A is an upstream 5' UTR variant (c.-666). The PTEN VCEP BP7 applies to synonymous or intronic variants at or beyond +7/-21 splice positions. This upstream variant is outside the BP7 scope. Details ▾Hide ▴
Evidence considered
  • Upstream variant c.-666
  • VCEP BP7 is for synonymous/intronic variants near splice sites.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • 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.
    Richards et al. 2015 ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a methodological framework paper; NM_000314.8:c.-666G>A is not discussed.
    Does not name this variant
    PMID 25741868 ↗
  • American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
    Saslow D et al. · 2007
    American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. Discusses breast cancer screening recommendations; NM_000314.8:c.-666G>A was not identified.
    Does not name this variant
    PMID 17392385 ↗
  • PTEN Hamartoma Tumor Syndrome.
    Adam MP et al. · 1993
    GeneReviews entry on PTEN Hamartoma Tumor Syndrome. Provides gene-level overview of PTEN-associated disorders and clinical management. NM_000314.8:c.-666G>A was not identified as a discussed variant.
    Does not name this variant
    PMID 20301661 ↗
  • Recommendations from the EGAPP Working Group: does PCA3 testing for the diagnosis and management of prostate cancer improve patient health outcomes?
    EGAPP Working Group recommendations on PCA3 testing for prostate cancer diagnosis and management. Not related to PTEN. NM_000314.8:c.-666G>A was not identified.
    Does not name this variant
    PMID 24071797 ↗
  • American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
    ASCO expert statement on collection and use of cancer family history for oncology providers. Discusses family history documentation practices. NM_000314.8:c.-666G>A was not identified.
    Does not name this variant
    PMID 24493721 ↗
  • Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board summary on Genetics of Breast and Gynecologic Cancers. Provides gene-level overview of cancer susceptibility genes including PTEN. NM_000314.8:c.-666G>A was not identified as a discussed variant.
    Does not name this variant
    PMID 26389210 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 109 / 386,848 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.040 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD 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.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00010901558922925978, 2/18346 alleles, homozygotes = 0).

ClinVar

This variant is present in ClinVar (Variation ID: 189528); submission details unavailable.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).