Abstract:
:While biallelic mutations in the PALB2 tumor suppressor cause Fanconi anemia subtype FA-N, monoallelic mutations predispose to breast and familial pancreatic cancer. Although hundreds of missense variants in PALB2 have been identified in patients to date, only a few have clear functional and clinical relevance. Herein, we investigate the effects of 44 PALB2 variants of uncertain significance found in breast cancer patients and provide detailed analysis by systematic functional assays. Our comprehensive functional analysis reveals two hotspots for potentially deleterious variations within PALB2, one at each terminus. PALB2 N-terminus variants p.P8L [c.23C>T], p.Y28C [c.83A>G], and p.R37H [c.110G>A] compromised PALB2-mediated homologous recombination. At the C-terminus, PALB2 variants p.L947F [c.2841G>T], p.L947S [c.2840T>C], and most strikingly p.T1030I [c.3089C>T] and p.W1140G [c.3418T>C], stood out with pronounced PARP inhibitor sensitivity and cytoplasmic accumulation in addition to marked defects in recruitment to DNA damage sites, interaction with BRCA2 and homologous recombination. Altogether, our findings show that a combination of functional assays is necessary to assess the impact of germline missense variants on PALB2 function, in order to guide proper classification of their deleteriousness.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Rodrigue A,Margaillan G,Torres Gomes T,Coulombe Y,Montalban G,da Costa E Silva Carvalho S,Milano L,Ducy M,De-Gregoriis G,Dellaire G,Araújo da Silva W Jr,Monteiro AN,Carvalho MA,Simard J,Masson JYdoi
10.1093/nar/gkz780subject
Has Abstractpub_date
2019-11-18 00:00:00pages
10662-10677issue
20eissn
0305-1048issn
1362-4962pii
5581727journal_volume
47pub_type
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