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NM_000314.8:c.488_492+5del
p.? · PTEN
ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 · v3.2
0%
complete
Final classification
VUS
PM2
PTEN
c.488_492+5del
p.?
unknown · exon 5-5i
Gene context NCBI Gene ↗ OncoKB ↗

PTEN is a tumor suppressor gene that encodes a phosphatase converting the lipid messenger PIP3 back to PIP2 at the cell membrane, thereby restraining the AKT/mTOR signaling pathway that drives cell growth, proliferation, and survival. It is one of the most frequently mutated genes across many types of human cancer, and its loss promotes unchecked cell growth, survival, and genomic instability, partly through impaired DNA repair. Germline loss-of-function variants in PTEN cause Cowden syndrome, an inherited cancer predisposition disorder associated with elevated risk of breast and thyroid cancer.

This variant

This PTEN splice-region deletion is relevant to an inherited tumor-predisposition gene whose loss disrupts PIP3-to-PIP2 signaling and promotes unchecked cell growth.

Transcript
NM_000314.8
HGVS · transcript:coding
NM_000314.8:c.488_492+5del
GRCh38
chr10:87933246 AAAAAGGTAAG>A
GRCh37
chr10:89693003 AAAAAGGTAAG>A
VUS: PM2 (supporting) was the only applied criterion, and no PTEN Expert Panel criteria-combination rule was satisfied.
Classification rationale
PM2 VUS
PTEN c.488_492+5del unknown · exon 5-5i

PM2 supporting: the variant is absent from gnomAD v2.1, v4.1, and available non-cancer subsets.

PM2 → VUS
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.
Gene diagram · NM_000314.8 · variants mapped to exon structure
PTEN NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 16 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
Met at supporting strength: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, below the PTEN PM2 threshold of <0.00001 allele frequency.
The PTEN Expert Panel specifies PM2 Supporting for allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population; where multiple alleles occur in a subpopulation, that frequency must be <0.00002 (0.002%).The variant search returned absent in GNOMAD_V2_1, GNOMAD_V4_1, GNOMAD_V2_1_NON_CANCER, and GNOMAD_V3_1_NON_CANCER, supporting an allele frequency of zero in each queried dataset.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
Assessed · not applied · 3 not met · 13 not assessed
Pathogenic
PVS1 Not assessed: SpliceAI max delta 0.994 predicts splice impact, but the resulting reading-frame consequence and NMD outcome are unestablished.
PS1 Not assessed: the intronic variant has protein consequence p.? and no established pathogenic same-amino-acid or same-position splice comparator is available.
PS2 Not assessed: no proband, parental-testing, maternity/paternity, or family-history data are available to establish a confirmed de novo occurrence.
PS3 Not assessed: no RNA or minigene assay result is available, and the governing missense phosphatase table contains no entry for this p.? splice-region deletion.
PS4 Not assessed: no case-control odds ratio is available to compare with the PTEN PS4 >2 threshold.
PM6 Not assessed: no affected proband, assumed de novo observation, parental-testing, or family-history data are available for PM6.
PP1 Not assessed: no affected relatives, segregation observations, family structure, or meiosis count are available for comparison with the 3-meiosis minimum.
PP3 Not assessed: SpliceAI max delta 0.994 exceeds 0.5, but the PTEN VCEP requires concordant SpliceAI and VarSeak results and VarSeak is unavailable.
Benign
BA1 Not met: the variant is absent from gnomAD v2.1, gnomAD v4.1, and non-cancer subsets, versus the PTEN BA1 threshold of >0.00056 allele frequency.
BS1 Not met: the variant is absent from all queried gnomAD datasets, versus the PTEN BS1 range of 0.0000043 to 0.00056 allele frequency.
BS2 Not assessed: no homozygous observation in a healthy or PHTS-unaffected individual is available to compare with the PTEN BS2 requirement.
BS3 Not assessed: no benign RNA or minigene assay result is available, and the governing missense phosphatase table contains no entry for this p.? splice-region deletion.
BS4 Not assessed: no affected-family-member genotypes or non-segregation observations are available to establish BS4 in one or more families.
BP2 Not assessed: no phase-resolved observation shows this variant in trans with a pathogenic PTEN variant or satisfies the three-observation cis/unknown-phase rule.
BP4 Not met: SpliceAI max delta 0.994 indicates splice impact and exceeds the <=0.1 BP4 threshold.
BP5 Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN histories are documented.
N/A · 11 PM1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
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.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
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.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99).
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