PALB2

Chr 16ADAR

partner and localizer of BRCA2

NCBI Gene: 79728ENSG00000083093UniProt: Q86YC2

Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks (PubMed:16793542, PubMed:19369211, PubMed:19423707, PubMed:22941656, PubMed:24141787, PubMed:28319063). Strongly stimulates the DNA strand-invasion activity of RAD51, stabilizes the nucleoprotein filament against a disruptive BRC3-BRC4 polypeptide and helps RAD51 to overcome the suppressive effect of replication protein A (RPA) (PubMed:20871615). Functionally cooperates with RAD51AP1 in promoting of D-loop formation by RAD51 (PubMed:20871616). Serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex which is essential for homologous recombination (PubMed:19369211). Via its WD repeats is proposed to scaffold a HR complex containing RAD51C and BRCA2 which is thought to play a role in HR-mediated DNA repair (PubMed:24141787). Essential partner of BRCA2 that promotes the localization and stability of BRCA2 (PubMed:16793542). Also enables its recombinational repair and checkpoint functions of BRCA2 (PubMed:16793542). May act by promoting stable association of BRCA2 with nuclear structures, allowing BRCA2 to escape the effects of proteasome-mediated degradation (PubMed:16793542). Binds DNA with high affinity for D loop, which comprises single-stranded, double-stranded and branched DNA structures (PubMed:20871616). May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with BRCA2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity (PubMed:24485656)

Primary Disease Associations & Inheritance

{Breast-ovarian cancer, familial, susceptibility to, 5}MIM #620442
AD
{Pancreatic cancer, susceptibility to, 3}MIM #613348
AD
Fanconi anemia, complementation group NMIM #610832
AR
UniProtBreast cancer
UniProtFanconi anemia complementation group N
UniProtPancreatic cancer 3
588
ClinVar variants
87
Pathogenic / LP
0.00
pLI score
12
Active trials
Clinical Summary— PALB2
🧬
Gene-Disease Validity (ClinGen)
Fanconi anemia complementation group N · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
87 Pathogenic / Likely Pathogenic· 196 VUS of 588 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.01LOEUF
pLI 0.000
Z-score 1.52
OE 0.76 (0.58–1.01)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.28Z-score
OE missense 0.97 (0.90–1.04)
568 obs / 586.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.76 (0.58–1.01)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.90–1.04)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06
0≤1.21.6
LoF obs/exp: 35 / 46.1Missense obs/exp: 568 / 586.8Syn Z: -0.73

ClinVar Variant Classifications

588 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic65
Likely Pathogenic22
VUS196
Likely Benign173
Benign122
Conflicting10
65
Pathogenic
22
Likely Pathogenic
196
VUS
173
Likely Benign
122
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
45
1
19
0
65
Likely Pathogenic
13
2
7
0
22
VUS
1
180
14
1
196
Likely Benign
0
17
73
83
173
Benign
0
0
25
97
122
Conflicting
—10
Total59200138181588

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PALB2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PALB2-related cancer

definitive
ADLoss Of FunctionAbsent Gene Product
Cancer
G2P ↗

PALB2-related Fanconi anemia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersCancer
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Breast-ovarian cancer, familial, susceptibility to, 5}

MIM #620442

Molecular basis of disorder known

Autosomal dominant

{Pancreatic cancer, susceptibility to, 3}

MIM #613348

Molecular basis of disorder known

Autosomal dominant

Fanconi anemia, complementation group N

MIM #610832

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PALB2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.
Breast Cancer Association Consortium et al.·N Engl J Med
2021
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.
Momozawa Y et al.·Nat Commun
2018Cohort
Pathogenic Germline Variants in 10,389 Adult Cancers.
Huang KL et al.·Cell
2018
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.
Susswein LR et al.·Genet Med
2016Cohort
Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer.
Okawa Y et al.·J Hepatol
2023
Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer.
Usui Y et al.·N Engl J Med
2023
NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024.
Daly MB et al.·J Natl Compr Canc Netw
2023
Homologous Recombination Deficiencies and Hereditary Tumors.
Yamamoto H et al.·Int J Mol Sci
2021Review
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
Decker B et al.·J Med Genet
2017
Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations.
Kuzbari Z et al.·Ann Oncol
2023Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
BRCA1/2, PALB2 mutations and first-line CDK4/6 inhibitor efficacy in HR+ metastatic breast cancer.
Guinel T et al.·Breast
2026🔓 Open Access
TBCRC 048 (Olaparib Expanded) Expansion Cohorts: Phase II Study of Olaparib Monotherapy for Patients With Metastatic Breast Cancer With Germline Mutations in PALB2 or Somatic Mutations in BRCA1 or BRCA2.
Tung NM et al.·J Clin Oncol
2026Cohort
Site-saturation functional screens identify PALB2 missense variants associated with increased breast cancer risk.
Boonen RACM et al.·Nat Commun
2026🔓 Open AccessFunctional
Pathogenic Germline PALB2 and RAD50 Variants in Patients With Relapsed Ewing Sarcoma.
Mack M et al.·Pediatr Blood Cancer
2026Cohort
Characterization of Copy Number Variants in Hereditary Cancer Patients Through NGS Shows a Distinctive PALB2 Contribution to the Diagnostic Yield.
Bonamici L et al.·Hum Mutat
2026🔓 Open AccessCohort
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Breast Cancer

Assessing Clinical Features and Outcome of Breast Cancer in PALB2 Mutation Carriers: the Palbreast Study

RECRUITING
NCT06403904Azienda Ospedaliero-Universitaria di ModenaStarted 2023-10-02
Breast CancerPALB2-Mutated Breast CarcinomaHER2-negative Breast Cancer

Phase Ib Study of Axatilimab in Combination With Olaparib in BRCA1/2 and PALB2- Associated Metastatic HER2-negative Breast Cancer

RECRUITING
NCT06488378Phase PHASE1Dana-Farber Cancer InstituteStarted 2024-08-13
AxatilimabOlaparib
Pancreas CancerPancreas CystPancreatic Ductal Adenocarcinoma

Pancreatic Cancer Early Detection Consortium

RECRUITING
NCT04970056Arbor Research Collaborative for HealthStarted 2020-09-18
Prostate CancerProstate BiopsyGenetic Counselling

The PROFILE Study: Germline Genetic Profiling: Correlation With Targeted Prostate Cancer Screening and Treatment

RECRUITING
NCT02543905Institute of Cancer Research, United KingdomStarted 2015-03-09
Prostate MRI and Biopsy
Pancreatic Cancer, Advanced or MetastaticBRCA1/2 MutationPALB2 Gene Mutation

Study of NABPLAGEM vs. Nab-Paclitaxel/Gemcitabine in BRCA1/2 or PALB2 Pancreatic Cancer

RECRUITING
NCT06783140Phase PHASE2, PHASE3University Health Network, TorontoStarted 2025-06-10
Nab paclitaxelGemcitabineCisplatin
Advanced Breast Cancer

FUnctional Selection of Advanced Breast Cancer Patients for Talazoparib Treatment Using the REpair Capacity (RECAP) Test

RECRUITING
NCT06193525Phase PHASE2Erasmus Medical CenterStarted 2019-09-16
Talazoparib
Prostate Cancer Metastatic Castration-ResistantAbnormal DNA RepairMetastatic Prostate Carcinoma

Abiraterone/Prednisone, Olaparib, or Abiraterone/Prednisone + Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Defects

ACTIVE NOT RECRUITING
NCT03012321Phase PHASE2Northwestern UniversityStarted 2017-01-12
OlaparibAbiraterone AcetatePrednisone
Breast Cancer Surgery

Long-term Safety of Nipple Sparing Mastectomy in Women With High Penetrance Breast Cancer Susceptibility Genes in Breast Cancer

RECRUITING
NCT06888388Sir Mortimer B. Davis - Jewish General HospitalStarted 2025-02-01
Nipple Sparing Mastectomy (NSM)Skin-Sparing Mastectomy (SSM)Total (Simple) Mastectomy
Breast CancerTriple Negative Breast Neoplasms

NordicTrip, a Translational Study of Preoperative Chemotherapy in TNBC

ACTIVE NOT RECRUITING
NCT04335669Phase PHASE3Lund University HospitalStarted 2019-12-20
epirubicin, cyclophosphamide, paclitaxel, carboplatin, pembrolizumabepirubicin, cyclophosphamide, capecitabine, paclitaxel, carboplatin, pembrolizumab
Stage I Breast CancerStage II Breast CancerStage III Breast Cancer

Niraparib + Dostarlimab In BRCA Mutated Breast Cancer

ACTIVE NOT RECRUITING
NCT04584255Phase PHASE2Dana-Farber Cancer InstituteStarted 2020-12-18
NiraparibDostarlimab
Solid CancersBRCA MutationHRD Cancer

A PARG Inhibitor DAT-2645 Monotherapy in Patients with Advanced/Metastatic Solid Tumors Harboring BRCA1/2 Loss of Function Alterations And/or Other Defects in the DDR Pathway

NOT YET RECRUITING
NCT06614751Phase PHASE1Danatlas Pharmaceuticals Co., LtdStarted 2024-11-01
DAT-2645 tabletDAT-2645 tablet
BRCA1 MutationBRCA2 MutationBRCA Mutation

Olaparib and ASTX727 in BRCA1/2- and Homologous Recombination Deficient (HRD)-Mutated Tumors

RECRUITING
NCT06177171Phase PHASE1Pamela MunsterStarted 2024-02-07
OlaparibASTX727

External Resources

Links to major genomics databases and tools