6:47

AnkiNex · card #17

Step 2 CK · Molecular Pathology · Hereditary Cancer Triad

PTEN genome Cowden syndrome

NM_000314.7(PTEN):c.388C>T

p.Arg130Ter · nonsense (PTC) · loss-of-function · AYA gastric ca / Cowden syndrome · cohort difficulty 0.72

ACMG/AMP 2015 Interpretation

PTEN c.388C>T is a null variant in PTEN. Loss-of-function mechanism established (Marsh 1999; Tan 2012). PVS1 + PM2_Supporting + PP4_Strong → Pathogenic.

Criterion

Strength

Evidence

PVS1

Strong

Null variant (nonsense, codon 130 of 403) in PTEN — established LoF mechanism (OMIM 601728; Eng 2003).

PM2_S

Supporting

Absent from gnomAD v4 non-cancer cohort (0 / 1.18M alleles).

PP4_S

Strong

AYA gastric carcinoma + macrocephaly + mucocutaneous papules — phenotype highly specific for PTEN-hamartoma tumor syndrome (PHTS, OMIM 158350).

Verdict

PATHOGENIC

PVS1 + PM2_Supporting + PP4_Strong → Pathogenic per Richards 2015 + ClinGen PTEN VCEP rules spec.

Why this card flags

142 MS3 cohort reviewers. 62% first-pass attempts pick mismatch repair. The answer hinges on PTEN → PI3K/AKT/mTOR pathway loss → epithelial proliferation in AYA gastric. Cohort difficulty 0.72 (top 3 of deck) → auto-flagged for ABOPM faculty re-review.

Anchors

ClinVar

VCV000128037 · 3-star reviewed by expert panel (ClinGen PTEN VCEP). Classification: Pathogenic.

clinvar.ncbi.nlm.nih.gov/variation/128037

ClinGen VCEP

PTEN Variant Curation Expert Panel · gene-specific rule spec applied (Mester 2018).

cspec.genome.network/cspec/ui/svi/affil/50039

COSMIC

PTEN tumor-suppressor (FGE entry CGC). Top mutated gene in Cowden + AYA glioma series.

cancer.sanger.ac.uk/cosmic/gene/PTEN

OMIM · MedGen

PHTS · OMIM 158350. Surveillance: annual breast / thyroid / endometrial / colorectal.

omim.org/entry/158350

Foundation One

F1CDx tumor profile report · PTEN c.388C>T detected at 48% allele frequency · TMB-low · MSS · HRD-positive signature.

F1CDx report · 2026-04-22

gnomAD

v4.1 non-cancer cohort · 0 / 1.18M alleles. Stratified breakdown across 7 ethnicities — absent in all.

gnomad.broadinstitute.org/variant/10-89711074-C-T

Faculty-signed by Adrienne, FACMG peer-review chain · case-001 referenced · 2026-04-29

hash: 7f3a4b…

Useful

Anchored my interpretation

LLAUDE0.1.0(2)

Marcus · MS3

show me the hardest PTEN AYA card this week

LAUDE

Calling cards.search + variant.pull_anchors… Card #17 · PTEN c.388C>T. Cohort difficulty 0.72. Pulling anchors: ClinVar/VCV000128037 · ClinGen/PTEN-VCEP · COSMIC/PTEN · OMIM/158350.

Marcus · MS3

why is this hard? what does the cohort miss?

LAUDE

Calling cohort.difficulty_signal… 62% first-pass pick mismatch repair. Correct path: PTEN → PI3K/AKT/mTOR → epithelial proliferation in AYA gastric. ACMG verdict PVS1 + PM2_S + PP4_S → Pathogenic per Richards 2015 + ClinGen PTEN VCEP.

Marcus · MS3

what's the tumor-side picture?

LAUDE

Pulling Foundation One F1CDx tumor profile for case-001 · PTEN c.388C>T at 48% VAF · TMB-low · MSS · HRD-positive signature. gnomAD v4.1 non-cancer: 0/1.18M alleles (absent across 7 ethnicities). Foundation report tacks to case-001 on merge.

Marcus · MS3

how do I add my own interpretation as evidence?

LAUDE

Tap "Anchored my interpretation" → fires ANKI_CARD_REVIEW. Your read tacks onto case-001's hash chain as new evidence. ABOPM faculty re-sign on cohort threshold. To generate NEW peer-signed evidence, open CaseChat and draft from a clinical narrative; I'll walk the ACMG/AMP criteria.

Ask LAUDE about this card…

Marcus is a medical student. New case on the floor — the 45F admitted last night.

LAUDE is the driver. The details are the evidence. He asks LAUDE for the hardest PTEN AYA card. LAUDE renders card #17 with the full ACMG/AMP table, ClinVar / ClinGen / COSMIC / OMIM anchors, faculty signature.

SLIDE ?? / ??

Student · MS3 · 6:47am · Hospital cafeteria

Marcus preps for rounds.

LAUDE is the driver

One natural-language prompt. LAUDE returns card #17 (PTEN c.388C>T) with full ACMG/AMP detail. The details are the evidence.

ACMG/AMP 2015 in one screen

PVS1 + PM2_Supporting + PP4_Strong → Pathogenic. Every criterion cites Richards 2015 + the ClinGen PTEN VCEP rules spec.

Anchors are real

ClinVar VCV000128037 (3★, ClinGen PTEN VCEP) · COSMIC FGE entry · OMIM 158350 (PHTS). Every anchor resolves to a public URL.

Cohort difficulty drives faculty re-review

0.72 cohort difficulty triggers ABOPM faculty re-review. Marcus's tap fires ANKI_CARD_REVIEW and hash-chains to case-001.

CANONIC Nexus

magic://hadleylab/ANKINEX/decks/step2ck-hereditary-triad/card-17

LEDGER · ANKI_CARD_REVIEW · COIN minted on signature