Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Journal Article
PMID (35853885)
Authors Wu S, Qi L, Chen H, Zhang K, He J, Guo X, Shen L, Zhou Y, Zhong X, Zheng S, Zhou J, Chen Y
Title Functional assessment of missense variants of uncertain significance in the cancer susceptibility gene PALB2.
URL
Abstract Text Germline PALB2 pathogenic variants are associated with an increased lifetime risk for breast, pancreatic, and ovarian cancer. However, the interpretation of the pathogenicity of numerous PALB2 missense variants of uncertain significance (VUSs) identified in germline genetic testing remains a challenge. Here we selected ten potentially pathogenic PALB2 VUSs identified in 2279 Chinese patients with breast cancer and evaluated their impacts on PALB2 function by systematic functional assays. We showed that three PALB2 VUSs p.K16M [c.47 A > T], p.L24F [c.72 G > C], and p.L35F [c.103 C > T] in the coiled-coil domain impaired PALB2-mediated homologous recombination. The p.L24F and p.L35F variants partially disrupted BRCA1-PALB2 interactions, reduced RAD51 foci formation in response to DNA damage, abrogated ionizing radiation-induced G2/M checkpoint maintenance, and conferred increased sensitivity to olaparib and cisplatin. The p.K16M variant presented mild effects on BRCA1-PALB2 interactions and RAD51 foci formation. Altogether, we identify two novel PALB2 VUSs, p.L24F and p.L35F, that compromise PALB2 function and may increase cancer risk. These two variants display marked olaparib and cisplatin sensitivity and may help predict response to targeted therapy in the clinical treatment of patients with these variants.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
PALB2 E1018D missense no effect - predicted PALB2 E1018D lies within WD repeat 4 of the Palb2 protein (UniProt.org). E1018D results in DNA damage-induced cell cycle checkpoint maintenance and homology-directed DNA repair activity similar to wild-type in cultured cells (PMID: 31757951, PMID: 35853885), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 K16M missense unknown PALB2 K16M lies within the DNA-binding, BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). K16M results in decreased Brca1 interaction, homology-directed DNA repair activity, and Palb2 and Rad51 foci formation in cultured cells, but maintains Rad51 binding, IR-induced G2/M checkpoint response, and rescues sensitivity to DNA-damaging agents to similar levels of wild-type protein in culture (PMID: 35853885), and therefore, its effect on Palb2 protein function is unknown.
PALB2 K628N missense no effect - predicted PALB2 K628N does not lie within any known functional domains of the Palb2 protein (UniProt.org). K628N results in homology-directed DNA repair activity similar to wild-type Palb2 in cultured cells (PMID: 35853885), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 L24F missense loss of function PALB2 L24F lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). L24F retains binding with Rad51 but confers a loss of function to Palb2 as demonstrated by decreased homology-directed DNA repair activity and Brca1 interaction, reduced Palb2 and Rad51 foci formation, increased sensitivity to DNA damaging agents, and failure to maintain an IR-induced G2/M checkpoint in cultured cells (PMID: 35853885).
PALB2 L35F missense loss of function PALB2 L35F lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). L35F retains binding with Rad51 but confers a loss of function to Palb2 as demonstrated by decreased homology-directed DNA repair activity and Brca1 interaction, reduced Palb2 and Rad51 foci formation, increased sensitivity to DNA damaging agents, and failure to maintain an IR-induced G2/M checkpoint in cultured cells (PMID: 35853885).
PALB2 P405A missense no effect - predicted PALB2 P405A lies within the DNA-binding and chromatin-association motif regions of the Palb2 protein (UniProt.org). P405A demonstrates homology-directed DNA repair activity similar to wild-type in cultured cells (PMID: 33811135, PMID: 35853885), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 R153W missense no effect - predicted PALB2 R153W lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). R153W results in homology-directed DNA repair activity similar to wild-type Palb2 in cultured cells (PMID: 35853885), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 R663C missense no effect - predicted PALB2 R663C does not lie within any known functional domains of the Palb2 protein (UniProt.org). R663C results in homology-directed DNA repair activity similar to wild-type Palb2 in cultured cells (PMID: 35853885), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 T1012I missense no effect - predicted PALB2 T1012I lies within WD repeat 4 of the Palb2 protein (UniProt.org). T1012I demonstrates homology-directed DNA repair activity similar to wild-type in cultured cells (PMID: 33811135, PMID: 35853885), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 T1099M missense no effect - predicted PALB2 T1099M lies within WD repeat 5 of the Palb2 protein (UniProt.org). T1099M results in homology-directed DNA repair activity similar to wild-type Palb2 in cultured cells (PMID: 35853885), and therefore, is predicted to have no effect on Palb2 protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PALB2 L35P PALB2 Y551* Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, expressing PALB2 L35P sensitized transformed human cells harboring PALB2 Y551* to Lynparza (olaparib) treatment in culture (PMID: 35853885). 35853885
PALB2 K16M PALB2 Y551* Advanced Solid Tumor no benefit Olaparib Preclinical - Cell culture Actionable In a preclinical study, expressing PALB2 K16M did not sensitize transformed human cells harboring PALB2 Y551* to Lynparza (olaparib) treatment in culture (PMID: 35853885). 35853885
PALB2 L35F PALB2 Y551* Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, expressing PALB2 L35F sensitized transformed human cells harboring PALB2 Y551* to Lynparza (olaparib) treatment in culture (PMID: 35853885). 35853885
PALB2 L24F PALB2 Y551* Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, expressing PALB2 L24F sensitized transformed human cells harboring PALB2 Y551* to Lynparza (olaparib) treatment in culture (PMID: 35853885). 35853885