GenemoderateQ35-encode-reanalysis

PALB2 (Q86YC2, 1,186 aa) - the physical link that makes BRCA1 and BRCA2 one pathway, named in 4 entries and never written; DepMap mean -0.339, statistically indistinguishable from CBX1 and MEN1, and its entire KMT2A intersection is one Ewing sarcoma germline paper

also called FANCN · partner and localizer of BRCA2

PALB2 is the bridge that holds the two famous breast-cancer proteins together, and without it they cannot work as one repair pathway. In this leukaemia it has essentially never been studied.

The same thing, for a scientist

**Named in 4 entries and never written.** PALB2 is the reason BRCA1 and BRCA2 are described as one pathway rather than two: it binds BRCA1's coiled-coil and BRCA2's N-terminus and physically couples the mediator step to the RAD51-loading step. **For this graph that matters because the consecutive-resection hypothesis treats BRCA1/BARD1 as licensing a downstream event, and PALB2 is the molecule that makes 'downstream' physical rather than metaphorical.** **The dependency is mid-range and lands in interesting company.** Mean Chronos -0.339 across 1,258 lines, 23.9% below -0.5 - close to CBX1 (-0.349) and MEN1 (-0.362), and markedly shallower than BRCA1 (-0.489) or BRCA2 (-0.519). **A gene whose only known job is to bridge two deep dependencies is itself a shallower one**, which is a real observation about pathway architecture and is recorded without an explanation. **In this disease, nothing.** `PALB2[tiab] AND KMT2A[tiab]` returns **1** - PMID 41549603, pathogenic germline PALB2 and RAD50 variants in relapsed Ewing sarcoma, which names KMT2A only in a panel. `PALB2[tiab] AND MLL[tiab]` returns **1** - PMID 24448499, an integrated germline-and-somatic analysis in ovarian cancer. **Neither is about this disease and neither measures PALB2 anywhere near the KMT2A locus.** No released ENCODE ChIP-seq experiment exists for PALB2.

Facts and figures

gene symbol	PALB2
uniprot	Q86YC2
uniprot entry name	PALB2_HUMAN
gene primary readback	PALB2
length AA	1186
protein name	Partner and localizer of BRCA2
how the accession was resolved	gene_exact:PALB2 AND organism_id:9606 AND reviewed:true returned exactly ONE reviewed record with primary gene name PALB2 (rules 62/65).
domains note	UniProt Q86YC2 declares no Domain features in the fields fetched; the coiled-coil that binds BRCA1 and the WD40 beta-propeller that binds BRCA2 are Coiled coil and Repeat features. data.domains is EMPTY rather than populated from recall.
localization	Nucleus (UniProt Q86YC2)
subnuclear localization	damage-induced nuclear foci colocalising with BRCA1 and BRCA2
localization shown for fusion	NO - nobody has looked in any fusion; no ENCODE ChIP-seq experiment exists
shown for fusion	NO - nobody has looked in any KMT2A fusion
cell type	not measured in a haematopoietic or KMT2A-rearranged cell
cell state	damage-conditional
epigenetic readout	none directly; PALB2 has a reported chromatin association through MRG15 but that was not verified in this beat and is not asserted here
depmap architecture note	PALB2 -0.339 sits between the two proteins it bridges, BRCA1 -0.489 and BRCA2 -0.519, and beside CBX1 -0.349 and MEN1 -0.362. All five from one call against one release.
encode status	NO released human TF ChIP-seq experiment for PALB2
absence class	never-measured
relationship to existing entries	gene-brca1 exists; gene-brca2 is written in this same tranche. PALB2 is the physical bridge between them and is written so the graph can state the BRCA1-to-BRCA2 step as a contact rather than as an ordering.

gene synonyms in uniprot

[
  "FANCN"
]

domains

[]

depmap

{
  "source": "Open Targets Platform 26.06 (meta.dataVersion year 26 month 06), fetched 2026-09-22",
  "gene_effect_metric": "Chronos",
  "n_screens_this_gene": 1258,
  "mean_gene_effect": -0.3392,
  "n_lines_below_minus_0_5": 300,
  "fraction_below_minus_0_5": 0.2385,
  "min": -1.2457,
  "max": 0.6085,
  "approvedSymbol_readback": "PALB2",
  "release_note": "rule 83: no release id in the payload, so the Open Targets dataVersion is recorded. Screen count is gene-specific (1258).",
  "no_median_split": "rule 84: no anti-selective-half tally reported.",
  "live_low_screen_control": "OR4F5 (ENSG00000186092), same session: approvedSymbol reads back but only 3 tissue blocks / 5 screens are returned - a passing symbol readback is not evidence the payload is populated."
}

bounded absence 2026 09 22

{
  "instrument": "PubMed esearch, one [tiab] tag per term, every querytranslation read back",
  "PALB2[tiab] AND KMT2A[tiab]": {
    "count": 1,
    "pmid": "41549603",
    "title_checked": "Pathogenic Germline PALB2 and RAD50 Variants in Patients With Relapsed Ewing Sarcoma - different disease, panel co-occurrence",
    "on_topic": 0
  },
  "PALB2[tiab] AND MLL[tiab]": {
    "count": 1,
    "pmid": "24448499",
    "title_checked": "Integrated analysis of germline and somatic variants in ovarian cancer - different disease, panel co-occurrence",
    "on_topic": 0
  },
  "name_list_searched": [
    "PALB2"
  ],
  "names_NOT_searched": [
    "FANCN",
    "'partner and localizer of BRCA2' as a phrase"
  ],
  "bounding_note": "rule 80 - titles and abstracts only; a PALB2 panel in a supplementary figure would be invisible.",
  "absence_class": "never-measured"
}

Still open

Why is the bridge a shallower dependency than either protein it bridges? A PALB2-independent BRCA2 loading route would explain it and would also weaken the consecutive-step reading of the resection cascade.
Is PALB2 mutated or lost at any rate in KMT2A-rearranged leukaemia? Two records, both in other diseases, is the entire literature.
Does PALB2's reported MRG15-mediated chromatin association place it on transcribed chromatin in a way that would interact with the H3K36me3/menin arm of this graph's hypothesis? That contact was not verified in this beat and is deliberately not asserted above.

Every source behind this entry (2)

E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
PALB2 physically links BRCA1 and BRCA2 in the DNA-damage response, so the two act as one pathway rather than as two independent steps.
PALB2 links BRCA1 and BRCA2 in the DNA-damage response. · Zhang F, et al. · Curr Biol 2009
PMID 19268590 DOI
What this evidence cannot show
Cell-line biochemistry and damage-induced focus formation in a non-haematopoietic system; no KMT2A, no fusion, no locus-level measurement.
Evidence that argues against this (1)
- A physical bridge does not establish that the two ends are consecutive steps of one reaction rather than parallel contributors, which is precisely the distinction this graph's consecutive-resection hypothesis turns on. The DepMap depths are also inconsistent with a strict one-pathway reading: a bridge whose loss is tolerated twice as well as either end's is not behaving like an obligate link. Broad Institute DepMap / Open Targets Platform 2026
E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
PALB2 has a mean DepMap Chronos gene effect of -0.339 across 1,258 lines with 23.9% below -0.5, shallower than both proteins it bridges (BRCA1 -0.489, BRCA2 -0.519) and close to CBX1 (-0.349) and MEN1 (-0.362), all from one call against one release.
DepMap CRISPR gene-effect (Chronos) for PALB2, served by the Open Targets Platform GraphQL API · Broad Institute DepMap / Open Targets Platform · Open Targets Platform 26.06 (meta.dataVersion year 26 month 06), fetched 2026-09-22 2026
What this evidence cannot show
Rule 83: Open Targets dataVersion 26.06 recorded in place of a DepMap release id; gene-specific screen count. Rule 84: no median-split proportion. The comparison to CBX1 and MEN1 is a similarity of numbers, not of biology, and is offered as context rather than as an inference.
Evidence that argues against this (1)
- Reading pathway architecture off relative Chronos depths is weak: differential guide efficiency, differential expression and differential paralogue buffering all move a mean without saying anything about position in a pathway. The observation is recorded; no mechanism is claimed from it. Broad Institute DepMap / Open Targets Platform 2026

Connected to

binds →BRCA1 (P38398, 1,863 aa) - named in 19 entries of this graph and never written: the HR mediator that CTCF and the H3K9 machinery are now reported to license at a break, and the only cascade member with a human therapy-related-leukaemia signal after topoisomerase II therapy
PALB2 binds the BRCA1 coiled-coil - the physical link
binds →BRCA2 (P51587, 3,418 aa) - the RAD51 loader that receives the resected end BRCA1 licensed, named in 10 entries and never written; DepMap mean -0.519, and its 12-record KMT2A intersection is entirely germline-panel and pan-cancer sequencing with no mechanism
PALB2 binds the BRCA2 N-terminus and localises it to damage
part of →What is left of the resection absence after the compute was done: the resting state is now MEASURED and negative in 13 ENCODE datasets, so the whole question collapses onto the DAMAGE state, which is never-measured for all six proteins in every cell type on Earth
never-measured at this locus; two literature records, both in other diseases