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Gene | PALB2 |
Variant | E669fs |
Impact List | frameshift |
Protein Effect | loss of function - predicted |
Gene Variant Descriptions | PALB2 E669fs results in a change in the amino acid sequence of the Palb2 protein beginning at aa 669 of 1186, likely resulting in premature truncation of the functional protein (UniProt.org). E669fs results in protein expression similar to wild-type Palb2, however, demonstrates impaired homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31757951), and therefore, is predicted to lead to a loss of Palb2 protein function. |
Associated Drug Resistance | |
Category Variants Paths |
PALB2 mutant PALB2 inact mut PALB2 E669fs |
Transcript | NM_024675.4 |
gDNA | chr16:g.(23630149_23630150) |
cDNA | c.(2005_2004) |
Protein | p.E669fs |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_001407298.1 | chr16:g.(23630149_23630150) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
XM_017023672 | chr16:g.(23630149_23630150) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
XM_017023673 | chr16:g.(23630149_23630150) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
NM_001407299.1 | chr16:g.(23630149_23630150) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
XM_011545946 | chr16:g.(23630155_23630156) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
XM_011545946.2 | chr16:g.(23630155_23630156) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
NM_024675.4 | chr16:g.(23630149_23630150) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
XM_017023673.2 | chr16:g.(23630149_23630150) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
NM_024675.3 | chr16:g.(23630149_23630150) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
NM_001407300.1 | chr16:g.(23630149_23630150) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
NM_024675 | chr16:g.(23630149_23630150) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
NM_001407302.1 | chr16:g.(23630149_23630150) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
NM_001407307.1 | chr16:g.(23621423_23621424) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
NM_001407297.1 | chr16:g.(23630149_23630150) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
XM_011545947.2 | chr16:g.(23630155_23630156) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
NM_001407301.1 | chr16:g.(23630149_23630150) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
XM_017023671 | chr16:g.(23630155_23630156) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
XM_011545947 | chr16:g.(23630155_23630156) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
XM_017023671.1 | chr16:g.(23630155_23630156) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
XM_017023672.2 | chr16:g.(23630149_23630150) | c.(2005_2004) | p.E669fs | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
PALB2 inact mut | pancreatic cancer | predicted - sensitive | Rucaparib | Case Reports/Case Series | Actionable | In a Phase II trial, maintenance Rubraca (rucaparib) resulted in a median progression-free survival (mPFS) of 13.1 months and an objective response rate (ORR) of 41.7% (15/36, 3 complete responses, 12 partial responses) in patients with platinum-sensitive, advanced pancreatic cancer harboring deleterious mutations in BRCA1/2 or PALB2, ORR was 50% (3/6) in patients with PALB2 mutations (PMID: 33970687; NCT03140670). | 33970687 |
PALB2 inact mut | prostate cancer | predicted - sensitive | Abiraterone + Niraparib + Prednisone | Phase III | Actionable | In a Phase III trial (MAGNITUDE), Zejula (niraparib) in combination with Zytiga (abiraterone) and Adasone (prednisone) (AAP) improved radiographic progression-free survival (HR 0.59) compared to placebo and AAP in patients with metastatic castration-resistant prostate cancer harboring inactivating mutations in the homologous recombination repair (HRR)-Fanconi pathway (BRIP1, FANCA, PALB2), with a HR of 0.59 in patients with PALB2 mutations (J Clin Oncol 40, no. 16_suppl (June 01, 2022) 5020; NCT03748641). | detail... |
PALB2 inact mut | prostate cancer | sensitive | Olaparib | Phase II | Actionable | In a Phase II (TOPARP-B) trial, Lynparza (olaparib) treatment resulted in a composite overall response rate of 57.1% (4/7) and a RECIST objective response rate of 33.3% (2/6) in patients with castration-resistant prostate cancer harboring deleterious PALB2 mutations (PMID: 31806540; NCT01682772). | 31806540 |
PALB2 inact mut | prostate cancer | sensitive | Olaparib | FDA approved - On Companion Diagnostic | Actionable | In a Phase III trial (PROfound) that supported FDA approval, Lynparza (olaparib) treatment significantly improved median imaging-based progression-free survival (5.8 vs 3.5 mo, HR 0.49, p<0.001) compared to control in patients with metastatic castration-resistant prostate cancer who progressed on hormone therapy and harbored deleterious or suspected deleterious mutations in homologous recombination repair genes, including PALB2 (PMID: 32343890; NCT02987543). | detail... detail... 32343890 |
PALB2 inact mut | prostate cancer | sensitive | Olaparib | Guideline | Actionable | Lynparza (olaparib) is included in guidelines as second-line therapy post androgen receptor-directed therapy for patients with metastatic castration-resistant prostate cancer harboring pathogenic mutations in PALB2 (NCCN.org). | detail... |
PALB2 inact mut | pancreatic ductal adenocarcinoma | no benefit | Cisplatin + Gemcitabine + Veliparib | Phase II | Actionable | In a Phase II trial, the addition of Veliparib (ABT-888) to Gemzar (gemcitabine) and Platinol (cisplatin) in pancreatic ductal adenocarcinoma patients with either a germline BRCA1, BRCA2, or PALB2 inactivating mutation did not improve response rate (RR) compared to Gemzar (gemcitabine) and Platinol (cisplatin) alone, with 74.1% (20/27) vs 65.2% (15/23), P=0.55, and led to similar median progression-free survival, 10.1 vs 9.7 mo, P=0.73, and median overall survival, 15.5 vs 16.4 mo, P=0.6 (PMID: 31976786). | 31976786 |
PALB2 inact mut | breast cancer | predicted - sensitive | Olaparib | Phase II | Actionable | In a Phase II trial (TBCRC 048), Lynparza (olaparib) treatment resulted in an objective response rate (ORR) of 33% (9/27) and a clinical benefit rate (CBR) at 18 weeks of 50% in patients with metastatic breast cancer harboring germline mutations in homologous recombination-related genes other than BRCA1/2, all responders harbored germline PALB2 inactivating mutations, ORR and CBR in PALB2-mutant patients (n=11) were 82% and 100%, respectively (PMID: 33119476; NCT03344965). | 33119476 |
PALB2 inact mut | pancreatic ductal adenocarcinoma | sensitive | Cisplatin + Gemcitabine | Phase II | Actionable | In a Phase II trial, patients with pancreatic ductal adenocarcinoma harboring either a germline BRCA1, BRCA2, or PALB2 inactivating mutation demonstrated a response rate of 65.2% (15/23), a median progression-free survival of 9.7 months, a median overall survival of 16.4 months, and a disease control rate of 78.3% (18/23) when treated with a combination of Gemzar (gemcitabine) and Platinol (cisplatin) (PMID: 31976786). | 31976786 |
PALB2 inact mut | Her2-receptor negative breast cancer | predicted - sensitive | Talazoparib | Case Reports/Case Series | Actionable | In a Phase II trial, Talzenna (talazoparib) treatment was well tolerated, and among 12 evaluable ERBB2 (HER2)-negative breast cancer patients with a homologous repair pathway mutation resulted in response in 25% (3/12) of patients, including two patients with germline mutations in PALB2, and resulted in stable disease for >/= 6 months in 3 patients, including one patient with a germline PALB2 mutation (J Clin Oncol 37, no. 15_suppl (May 20, 2019) 3006). | detail... |
PALB2 inact mut | prostate cancer | predicted - sensitive | Rucaparib | Case Reports/Case Series | Actionable | In a Phase II trial (TRITON2), 2 of 2 patients with metastatic castrate-resistant prostate cancer harboring deleterious PALB2 alterations demonstrated a PSA response after treatment with Rubraca (rucaparib), with one of those patients demonstrating partial radiographic response that was ongoing 3.9 months, and the other a 47% reduction in tumor volume (PMID: 32086346; NCT02952534). | 32086346 |
PALB2 inact mut | estrogen-receptor positive breast cancer | sensitive | Talazoparib | Guideline | Actionable | Talzenna (talazoparib) is included in guidelines as second-line therapy for patients with ESR1 (ER)-positive, ERBB2 (HER2)-negative metastatic breast cancer with germline or somatic pathogenic/likely pathogenic PALB2 mutations who have progressed on an endocrine therapy plus CDK4/6 inhibitor (PMID: 34678411; ESMO.org). | 34678411 detail... |
PALB2 inact mut | Advanced Solid Tumor | sensitive | Olaparib | Preclinical | Actionable | In a preclinical study, Lynparza (olaparib) resulted in decreased cell survival in a PALB2 deficient cell line derived from a Fanconi anemia patient (PMID: 20871615). | 20871615 |
PALB2 inact mut | biliary tract cancer | sensitive | Rucaparib | Guideline | Actionable | Rubraca (rucaparib) is included in guidelines as second or later-line therapy for patients with biliary tract cancer harboring BRCA1/2 mutations (PMID: 36372281; ESMO.org). | detail... 36372281 |
PALB2 inact mut | prostate cancer | sensitive | Enzalutamide + Talazoparib | FDA approved | Actionable | In a Phase III trial (TALAPRO-2) that supported FDA approval, Talzenna (talazoparib) plus Xtandi (enzalutamide) improved median radiographic progression-free survival compared to enzalutamide plus placebo (27.9 vs 16.4 mo, HR 0.46, p=0.0003) in patients with metastatic castration-resistant prostate cancer harboring deficient homologous recombination repair genes including PALB2, with an HR of 0.66 (p=0.12) in patients with non-BRCA mutations treated with Talzenna (talazoparib) (PMID: 37285865; NCT03395197). | 37285865 detail... |
PALB2 inact mut | prostate cancer | sensitive | Enzalutamide + Talazoparib | Guideline | Actionable | Talzenna (talazoparib) plus Xtandi (enzalutamide) is included in guidelines as systemic therapy for patients with metastatic castration-resistant prostate cancer harboring a pathogenic germline or somatic PALB2 mutation who have not been treated in the setting of castration-resistant prostate cancer (NCCN.org). | detail... |
PALB2 inact mut | estrogen-receptor positive breast cancer | sensitive | Olaparib | Guideline | Actionable | Lynparza (olaparib) is included in guidelines as second-line therapy for patients with ESR1 (ER)-positive, ERBB2 (HER2)-negative metastatic breast cancer with germline or somatic pathogenic/likely pathogenic PALB2 mutations who have progressed on an endocrine therapy plus CDK4/6 inhibitor (PMID: 34678411; ESMO.org). | detail... 34678411 |
PALB2 inact mut | Her2-receptor negative breast cancer | sensitive | Olaparib | Guideline | Actionable | Lynparza (olaparib) is included in the Pan-Asian Guidelines Adaptation (PAGA) as second-line therapy for patients with hormone receptor-positive, ERBB2 (HER2)-negative metastatic breast cancer with germline pathogenic/likely pathogenic PALB2 mutations who have progressed on an endocrine therapy plus CDK4/6 inhibitor (PMID: 37178669; ESMO.org). | 37178669 detail... |
PALB2 inact mut | triple-receptor negative breast cancer | predicted - sensitive | Ceralasertib + Olaparib | Case Reports/Case Series | Actionable | In a Phase II trial (plasmaMATCH), treatment with the combination of Lynparza (olaparib) and Ceralasertib (AZD6738) resulted in limited efficacy in patients with advanced triple-negative breast cancer, with an objective response rate of 17.1% (12/70), including a complete response in a patient with a germline mutation in PALB2 (PMID: 37773077; NCT03182634). | 37773077 |
PALB2 mutant | pancreatic cancer | not applicable | N/A | Guideline | Risk Factor | Germline PALB2 mutations are associated with increased pancreatic cancer susceptibility (NCCN.org). | detail... |
PALB2 mutant | pancreatic adenocarcinoma | sensitive | Rucaparib | Guideline | Actionable | Rubraca (rucaparib) is included in guidelines as maintenance therapy following prior platinum-based therapy for patients with metastatic pancreatic adenocarcinoma harboring germline PALB2 mutations (NCCN.org). | detail... |
PALB2 mutant | pancreatic cancer | predicted - sensitive | Talazoparib | Case Reports/Case Series | Actionable | In a Phase I trial, Talzenna (talazoparib) treatment resulted in an objective response rate of 20.0% (2/10, 2 partial responses) and a clinical benefit rate of 30.0% in patients with pancreatic cancer, including a partial response in one patient harboring a PALB2 mutation (PMID: 28242752; NCT01286987). | 28242752 |
PALB2 mutant | prostate cancer | not applicable | N/A | Guideline | Risk Factor | Germline PALB2 mutations are associated with increased risk of developing prostate cancer (NCCN.org). | detail... |
PALB2 mutant | pancreatic adenocarcinoma | sensitive | Cisplatin + Gemcitabine | Guideline | Actionable | Platinol (cisplatin), in combination with Gemzar (gemcitabine), is included in guidelines as a preferred first-line therapy for patients with locally advanced or metastatic pancreatic adenocarcinoma harboring PALB2 mutations with good performance status (ECOG 0 -1), and as a subsequent therapy for patients with locally advanced, metastatic, or recurrent diseases (NCCN.org). | detail... |
PALB2 mutant | pancreatic adenocarcinoma | sensitive | Fluorouracil + Irinotecan + Leucovorin + Oxaliplatin | Guideline | Actionable | FOLFIRINOX is included in guidelines as a preferred first-line therapy for patients with locally advanced or metastatic pancreatic adenocarcinoma harboring PALB2 mutations with good performance status (ECOG 0 -1) (NCCN.org). | detail... |
PALB2 mutant | uveal melanoma | not applicable | N/A | Guideline | Risk Factor | Germline PALB2 mutations are associated with familial uveal melanoma and increased risk of developing uveal melanoma (NCCN.org). | detail... |