PALB2-related cancer predisposition

Summary

PALB2-related cancer predisposition (MONDO:0700272) is a cancer caused by PALB2 (GenCC Definitive), with 1 cohort gene (1 CIViC-evidence somatic driver; 71 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Causal gene: PALB2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 71

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	PALB2-related cancer predisposition
Mondo ID	MONDO:0700272
GARD	0026412
Is cancer (heuristic)	yes

Data availability: 71 ClinVar variants · 39 ClinGen variant curations · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › PALB2-related cancer predisposition

Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, blue rubber bleb nevus, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, Rothmund-Thomson syndrome, mismatch repair cancer syndrome 1, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, Kostmann syndrome, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 3, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, colorectal cancer, susceptibility to, 12, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, DDX41-related hematologic malignancy predisposition syndrome, nasopharyngeal carcinoma, susceptibility to, 3, familial isolated hyperparathyroidism, intestinal polyposis syndrome, dyskeratosis congenita, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, leukemia, acute myeloid, susceptibility to, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, CDH1-related diffuse gastric and lobular breast cancer syndrome, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, tumor predisposition syndrome 2, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

Subtypes (1): pancreatic cancer, susceptibility to, 3

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

71 retrieved; paginated sample, class counts are floors:

22 pathogenic, 15 uncertain significance, 10 pathogenic/likely pathogenic, 9 conflicting classifications of pathogenicity, 5 benign, 5 likely pathogenic, 4 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1245	NM_024675.4(PALB2):c.3549C>G (p.Tyr1183Ter)	PALB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126598	NM_024675.4(PALB2):c.1317del (p.Phe440fs)	PALB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126609	NM_024675.4(PALB2):c.1592del (p.Leu531fs)	PALB2	Pathogenic	reviewed by expert panel
126644	NM_024675.4(PALB2):c.229del (p.Cys77fs)	PALB2	Pathogenic	criteria provided, multiple submitters, no conflicts
126688	NM_024675.4(PALB2):c.2835-1G>C	PALB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126711	NM_024675.4(PALB2):c.3113G>A (p.Trp1038Ter)	PALB2	Pathogenic	reviewed by expert panel
126715	NM_024675.4(PALB2):c.3116del (p.Asn1039fs)	PALB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126767	NM_024675.4(PALB2):c.751C>T (p.Gln251Ter)	PALB2	Pathogenic	criteria provided, multiple submitters, no conflicts
128128	NM_024675.4(PALB2):c.2120del (p.Pro707fs)	PALB2	Pathogenic	criteria provided, multiple submitters, no conflicts
128142	NM_024675.4(PALB2):c.3456dup (p.Pro1153fs)	PALB2	Pathogenic	criteria provided, multiple submitters, no conflicts
128144	NM_024675.4(PALB2):c.3549C>A (p.Tyr1183Ter)	PALB2	Pathogenic	reviewed by expert panel
141560	NM_024675.4(PALB2):c.2964del (p.Gln988_Val989insTer)	PALB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1453402	NM_024675.4(PALB2):c.2787_2788dup (p.Asn930fs)	PALB2	Pathogenic	reviewed by expert panel
186990	NM_024675.4(PALB2):c.2524_2535delinsTCAGA (p.Ala842fs)	PALB2	Pathogenic	reviewed by expert panel
2001574	NM_024675.4(PALB2):c.2278del (p.Ala761fs)	PALB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216121	NM_024675.4(PALB2):c.2470dup (p.Cys824fs)	PALB2	Pathogenic	criteria provided, multiple submitters, no conflicts
220371	NM_024675.4(PALB2):c.93dup (p.Leu32fs)	PALB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
231961	NM_024675.4(PALB2):c.3113+5G>C	PALB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
232398	NM_024675.4(PALB2):c.1216del (p.Ala406fs)	PALB2	Pathogenic	criteria provided, multiple submitters, no conflicts
232594	NM_024675.4(PALB2):c.3350G>A (p.Arg1117Lys)	PALB2	Pathogenic	reviewed by expert panel
232803	NM_024675.4(PALB2):c.2325dup (p.Phe776fs)	PALB2	Pathogenic	criteria provided, multiple submitters, no conflicts
241571	NM_024675.4(PALB2):c.7G>T (p.Glu3Ter)	PALB2	Pathogenic	reviewed by expert panel
2498119	NC_000016.10:g.(?23603162)(23603669_?)del	PALB2	Pathogenic	reviewed by expert panel
2573229	NM_024675.4(PALB2):c.1560C>A (p.Cys520Ter)	PALB2	Pathogenic	criteria provided, multiple submitters, no conflicts
461007	NM_024675.4(PALB2):c.514_517del (p.Ser172fs)	PALB2	Pathogenic	reviewed by expert panel
480243	NM_024675.4(PALB2):c.839del (p.Asn280fs)	PALB2	Pathogenic	reviewed by expert panel
484222	NM_024675.4(PALB2):c.682C>T (p.Gln228Ter)	PALB2	Pathogenic	reviewed by expert panel
484236	NM_024675.4(PALB2):c.1266del (p.Lys422_Val423insTer)	PALB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
492193	NM_024675.4(PALB2):c.2607dup (p.Val870fs)	PALB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
565404	NM_024675.4(PALB2):c.3008dup (p.Asn1003fs)	PALB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
PALB2	LoF	OVT	CIViC #15013

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PALB2	Definitive	Autosomal dominant	PALB2-related cancer predisposition	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PALB2	Orphanet:1333	Familial pancreatic carcinoma
PALB2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PALB2	Orphanet:178	Chordoma
PALB2	Orphanet:227535	Hereditary breast cancer
PALB2	Orphanet:84	Fanconi anemia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PALB2	HGNC:26144	ENSG00000083093	Q86YC2	Partner and localizer of BRCA2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PALB2	Partner and localizer of BRCA2	Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PALB2	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PALB2	232	ubiquitous	yes	secondary oocyte, buccal mucosa cell, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PALB2	5,641

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PALB2	Q86YC2	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Impaired BRCA2 binding to PALB2	1	456.8×	0.004	PALB2
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	423.0×	0.004	PALB2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	423.0×	0.004	PALB2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	423.0×	0.004	PALB2
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	393.8×	0.004	PALB2
Homologous DNA Pairing and Strand Exchange	1	380.7×	0.004	PALB2
Resolution of D-loop Structures through Holliday Junction Intermediates	1	300.5×	0.005	PALB2
HDR through Homologous Recombination (HRR)	1	190.3×	0.007	PALB2
KEAP1-NFE2L2 pathway	1	120.2×	0.009	PALB2
Neddylation	1	47.4×	0.021	PALB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
inner cell mass cell proliferation	1	991.3×	0.005	PALB2
post-anal tail morphogenesis	1	732.7×	0.005	PALB2
mesoderm development	1	526.6×	0.005	PALB2
embryonic organ development	1	481.5×	0.005	PALB2
somitogenesis	1	374.5×	0.005	PALB2
animal organ morphogenesis	1	191.5×	0.009	PALB2
double-strand break repair via homologous recombination	1	156.0×	0.009	PALB2
multicellular organism growth	1	137.0×	0.009	PALB2
negative regulation of apoptotic process	1	34.8×	0.032	PALB2
apoptotic process	1	28.7×	0.035	PALB2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PALB2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Drug repurposing candidates

0 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PALB2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PALB2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.