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NM_000314.8:c.276_277insG
p.His93AlafsTer2 · PTEN
ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 · v3.2
0%
complete
Final classification
Pathogenic
PVS1PM1PM2
PTEN
c.276_277insG
p.His93AlafsTer2
frameshift · exon 5
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 loss-of-function variant is relevant to Cowden syndrome, an inherited cancer predisposition disorder caused by impaired tumor-suppressor activity and associated with elevated breast and thyroid cancer risk.

Transcript
NM_000314.8
HGVS · transcript:coding
NM_000314.8:c.276_277insG
GRCh38
chr10:87933035 C>CG
GRCh37
chr10:89692792 C>CG
Pathogenic: PVS1 (very strong), PM1 (moderate), and PM2 (supporting) satisfy Rule3 of the PTEN Expert Panel Version 3.2 framework.
Classification rationale
PVS1PM1PM2 Pathogenic
PTEN c.276_277insG frameshift · exon 5

Pathogenic: PVS1 is very strong because the frameshift truncates PTEN at His93 before the VCEP NMD threshold. Pathogenic: PM1 is moderate because the frameshift begins within the PTEN VCEP critical interval at residues 90-94. Pathogenic: PM2 is supporting because the variant is absent from gnomAD v2.1 and v4.1.

PVS1 + PM1 + PM2 → Pathogenic
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 · 3 applied · 12 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 · 3
Strength Supporting Moderate Strong Very strong
PVS1 very strong Pathogenic
Met, very strong: the frameshift truncates PTEN at His93, well before the VCEP p.D375 (c.1121) NMD threshold.
The case normalization identifies NM_000314.8:c.276_277insG as a frameshift yielding NP_000305.3:p.(His93AlafsTer2) / p.(H93Afs*2), beginning at amino-acid residue 93.The PTEN VCEP decision tree specifies PVS1 for nonsense or frameshift variants in biologically relevant NM_000314.8 when the stop codon or disruption is at or 5' to p.D375 (c.1121) and NMD is predicted.The ClinGen PTEN specification directs users to the PTEN PVS1 decision tree for PVS1 strength assignment; this variant is not a canonical splice-site variant and no VCEP downgrade rule is triggered.
cspec ↗
PM1 moderate review Pathogenic
Met, moderate: the frameshift starts at His93, within the PTEN VCEP critical interval 90-94, and H93 is recorded as a statistically significant hotspot.
The PTEN VCEP PM1 rule defines critical catalytic-motif residues 90-94, 123-130, and 166-168 on NP_000305.3.The variant is NP_000305.3:p.(H93Afs*2), so the frameshift begins at residue His93 within the VCEP interval 90-94.The case evidence records PTEN H93 as a statistically significant hotspot, although the hotspot extraction is flagged as partial.
cspec ↗
PM2 supporting Pathogenic
Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN PM2 requirement of allele frequency below 0.00001.
The PTEN VCEP specifies PM2 at supporting strength for allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population, with a <0.00002 (0.002%) subpopulation condition when multiple alleles are present.The variant NM_000314.8:c.276_277insG is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed allele frequency of zero in each queried dataset.The PTEN VCEP does not specify a non-cancer or exome-only source for PM2, so all-comers gnomAD results are used.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
Assessed · not applied · 3 not met · 9 not assessed
Pathogenic
PS2 Not assessed: no documented parental testing establishes a confirmed de novo occurrence for the proband.
PS3 Not assessed: the PTEN VCEP assay table contains no entry for this frameshift, and its <= -1.11 PS3_Moderate threshold applies only to exact high-confidence missense results.
PS4 Not assessed: no case-control enrichment statistics or PTEN phenotype-specific proband score is available to compare with the VCEP PS4 thresholds.
PM6 Not assessed: no documented presumed de novo observation in an affected proband is available for PM6.
PP1 Not assessed: no affected relatives or informative meioses are documented to evaluate cosegregation.
Benign
BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the PTEN BA1 threshold of 0.00056.
BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, so its frequency does not reach the PTEN BS1 lower threshold of 0.000043.
BS2 Not met: no homozygous observation in a healthy or PHTS-unaffected individual is reported, and the variant is absent from gnomAD v2.1 and v4.1.
BS3 Not assessed: no variant-specific benign assay result was found, and the VCEP's >0 BS3 threshold applies to an exact missense assay entry absent for this frameshift.
BS4 Not assessed: no affected relatives with documented non-segregation are available to support BS4.
BP2 Not assessed: no documented cis, trans, or phase-unknown observation with a pathogenic or likely pathogenic PTEN variant is available.
BP5 Not assessed: two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN history are not documented.
N/A · 13 PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · PP4 · PP5 · BP1 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
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 = 0.04).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant lies in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 2 PMIDs not cited in assessment
11237521 ↗ PTEN: life as a tumor suppressor. ONCOKB
17218262 ↗ Essential role for nuclear PTEN in maintaining chromosomal integrity. ONCOKB