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NM_000314.8:c.-326_-324delinsCCC
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.-326_-324delinsCCC
p.?
unknown · exon 1
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

As a noncoding PTEN variant, this change is relevant to assessment of a tumor-suppressor gene in which germline loss of function causes Cowden syndrome and related cancer predisposition.

Transcript
NM_000314.8
HGVS · transcript:coding
NM_000314.8:c.-326_-324delinsCCC
GRCh38
chr10:87864144 GCG>CCC
GRCh37
chr10:89623901 GCG>CCC
VUS: PM2 (supporting) is met, but no PTEN Expert Panel combination rule is satisfied by the adjudicated criteria.
Classification rationale
PM2 VUS
PTEN c.-326_-324delinsCCC unknown · exon 1

PM2 supports the classification at Supporting strength because the variant is absent from gnomAD v2.1 and v4.1.

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 · 14 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: the variant is absent from gnomAD v2.1 and v4.1, satisfying the VCEP requirement for <0.00001 (0.001%) allele frequency.
ClinGen PTEN VCEP Version 3.2, PM2 Supporting rule: databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population; if multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%).gnomAD v2.1 result for NC_000010.10:g.89623901_89623903delinsCCC: absent.gnomAD v4.1 result for NC_000010.11:g.87864144_87864146delinsCCC: absent.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
Assessed · not applied · 2 not met · 12 not assessed
Pathogenic
PS2 Not assessed: no proband de novo observation, parental testing, maternity/paternity confirmation, disease phenotype, or family-history information is available.
PS3 Not assessed: the governing mmc2.xlsx search found no c.-326_-324delinsCCC or p.? entry and no case-specific damaging functional result is available.
PS4 Not assessed: no case-control statistics or qualifying proband phenotype-specificity scores are available to compare with the PTEN VCEP PS4 thresholds.
PM6 Not assessed: no de novo observations, proband disease phenotype, family history, or parental testing information is available to evaluate PM6 thresholds.
PP1 Not assessed: no affected relatives, segregation observations, family structure, or meiosis count is available for evaluating PP1.
PP3 Not assessed: the PTEN rule requires concordance of SpliceAl and VarSeak for splicing variants, but only SpliceAI (maximum delta 0.015) is available.
Benign
BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the >0.00056 (0.056%) BA1 threshold.
BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, so its frequency does not fall within either 0.0000043–0.00056 BS1 interval.
BS2 Not assessed: gnomAD reports absence and provides no confirmed or unconfirmed homozygous observations in healthy or PHTS-unaffected individuals.
BS3 Not assessed: mmc2.xlsx contains no matching c.-326_-324delinsCCC or p.? entry and provides no variant-specific phosphatase activity >0 value.
BS4 Not assessed: no affected-family-member genotypes or segregation results are available to evaluate lack of segregation in one or more families.
BP2 Not assessed: no affected-proband, phase, or cis/trans observations pairing this variant with a pathogenic or likely pathogenic PTEN variant are available.
BP4 Not assessed: the PTEN rule requires concordance of SpliceAl and VarSeak for splicing variants, but only SpliceAI (maximum delta 0.015) is available.
BP5 Not assessed: no two qualifying cases with a highly penetrant alternate disorder and non-overlapping PTEN history are documented.
N/A · 13 PVS1 · PS1 · 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
Not available in 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 no significant splice impact for this variant (max delta score = 0.01).
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