11:18

OmicsNex · cls-brca1-c5266dupc

ACMG/AMP 2015 · ClinGen ENIGMA BRCA1 VCEP rules-spec v1.1.0

BRCA1 17q21.31 germline Tumor suppressor HBOC

NM_007294.4(BRCA1):c.5266dupC

p.Gln1756ProfsTer74 · frameshift exon 20/23 · founder allele · case-001 (45F, mixed Caribbean + Sephardic) · 3 carriers / 14 mo @ MSMC

PATHOGENIC · ENIGMA VCEP curated · ClinVar VCV000055638 · 4-star

ACMG/AMP 2015 · ENIGMA BRCA1 VCEP rules-spec

Crit

Str

Evidence + rules-spec citation

Pts

PVS1

Strong

Null variant (frameshift, premature stop) in BRCA1 — established LoF mechanism (OMIM 113705; Tavtigian 2018). Variant before last 50nt of penultimate exon — NMD-predicted per VCEP decision tree. ENIGMA rules-spec v1.1.0 § PVS1.frameshift.

PM2_S

Supporting

gnomAD v4 non-cancer: 1 het / 1.3M alleles (AF 7.7e-7). Stratified absent in nfe/sas/amr/afr/fin/asj; 1 het in mid (Middle Eastern). ENIGMA § PM2_Supporting — Supporting downgrade per VCEP.

PP4_S

Strong

Phenotype-genotype match upgraded: 3 unrelated Caribbean+Sephardic carriers in 14 mo at MSMC (case-001/007/014). All bilateral breast Ca, strong family hx ovarian; founder context in Iraqi/Mizrahi cohorts (Levanon 1997, Gabai-Kapara 2014). ENIGMA § PP4_Strong threshold met.

BS1

Not met

AF 7.7e-7 below disease cutoff. ENIGMA § BS1 cutoff 1e-4 not invoked.

—

PS3

Not invoked

SGE function score −1.68 (Findlay 2018) available; not double-counted with PVS1 per VCEP rules.

—

In-silico predictions

BayesDel

0.847

Deleterious · max threshold

REVEL

N/A

SNV-only · frameshift

AlphaMissense

N/A

missense-only

SpliceAI

Δ 0.12

No splice effect

Functional evidence + provider anchors

Findlay SGE

Saturation genome editing, HAP1 cells. Function score −1.68 = loss-of-function. doi:10.1038/s41586-018-0461-z

ClinVar 4★

VCV000055638 · ENIGMA expert panel · Pathogenic since 2018 · 12 submitters, 0 conflicts. clinvar/55638

COSMIC

FGE entry · BRCA1 tumor suppressor · 87 distinct LoF variants reported in HBOC. cosmic/BRCA1

Family pedigree + cohort context

Proband · case-001

45F · bilateral breast Ca · BRCA1 c.5266dupC heterozygous. Mother d. ovarian Ca age 52 (untested). Maternal aunt breast Ca age 38 (untested). Cascade flagged — daughter age 38.

Cohort · MSMC south-FL

3rd Caribbean+Sephardic carrier in 14 mo. case-007: 51F bilat breast (Cuban-Sephardic). case-014: 47F unilat + ovarian (Cuban-Mizrahi). Cohort tag south-fl-caribbean-sephardic. 0 published cohorts in this admixture.

Anchor my reading

Submit + queue peer-sign (@anil, @irman)

LLAUDE0.1.0(2)

Adrienne · FACMG

classify BRCA1 c.5266dupC under ENIGMA VCEP

LAUDE

Calling variant.pull_anchors + vcep.rules_spec(ENIGMA,BRCA1) + gnomad.stratified_freq… ClinVar VCV000055638 4★. Findlay SGE function −1.68. gnomAD v4 stratified: 1 het mid, absent everywhere else.

Adrienne · FACMG

walk the rules + check our cohort threshold

LAUDE

PVS1 Strong: frameshift, NMD-predicted. PM2_S: 1/1.3M, VCEP downgrade. PP4_S: 3 Caribbean+Sephardic carriers in 14 mo → VCEP PP4 strong threshold met. Combined: Pathogenic. BS1 not invoked (AF below cutoff). PS3 available but not double-counted with PVS1.

Adrienne · FACMG

cohort gap + downstream?

LAUDE

Calling cohort.gap_check… 0 published Sephardic + Caribbean admixture cohorts. This classification fills the gap. Foundation One on case-001 = HRD-positive → CPIC PARP-i Tier-1A merges. ClinVar resubmission queued under ENIGMA VCEP.

Adrienne · FACMG

submit + queue peer-sign

LAUDE

Calling classification.submit… CLASSIFY fired. Hash anchored. Peer-sign queued for @anil (ABOPM) + @irman (FACMG · MSMC). On 2nd signature: cls-brca1-c5266dupc binds bidirectionally to case-001; PARP-i Tier-1A merges; ClinVar resubmission under ENIGMA VCEP.

Sign as third reviewer…

Adrienne classifies. The Illumina panel returned BRCA1 c.5266dupC.

Genetics consult, 11:18am. She opens OmicsNex. LAUDE walks the ACMG/AMP 2015 rules under the ClinGen ENIGMA BRCA1 VCEP rules-spec — functional assays, gnomAD non-cancer stratification, in-silico predictions, family-pedigree cohort. PVS1 + PM2_Supporting + PP4_Strong → Pathogenic. Submit queues peer-sign for Anil + Irman.

SLIDE ?? / ??

Specialist · FACMG · 11:18am · Genetics consult

Adrienne classifies.

ENIGMA VCEP rules-spec walked end-to-end

PVS1 + PM2_Supporting + PP4_Strong → Pathogenic. Every criterion cites the rules-spec line; BS1 + PS3 explicitly considered and dismissed under VCEP guidance.

Functional + in-silico anchored

Findlay SGE −1.68 (LoF) · BayesDel 0.847 · SpliceAI no effect · ClinVar 4-star (ENIGMA expert panel) · COSMIC FGE entry. Every anchor public.

Cohort is novel evidence, not a footnote

3 mixed Caribbean+Sephardic carriers in 14 mo at MSMC. 0 published cohorts in this admixture. case-001 is the fill — and the byline.

Submit fires the ledger chain

CLASSIFY on submit. Peer-sign queue: @anil (ABOPM) + @irman (FACMG · MSMC). On 2nd signature: bidirectional bind to case-001; ClinVar resubmission under ENIGMA VCEP.

CANONIC Nexus

magic://hadleylab/OMICSNEX/cls-brca1-c5266dupc

LEDGER · CLASSIFY · CASE_PEER_REVIEW_SIGNED · ClinVar resubmit queue