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Ref Type Journal Article
PMID (31636395)
Authors Wiltshire T, Ducy M, Foo TK, Hu C, Lee KY, Belur Nagaraj A, Rodrigue A, Gomes TT, Simard J, Monteiro ANA, Xia B, Carvalho MA, Masson JY, Couch FJ
Title Functional characterization of 84 PALB2 variants of uncertain significance.
Journal Genetics in medicine : official journal of the American College of Medical Genetics
Vol
Issue
Date 2019 Oct 21
URL
Abstract Text Inherited pathogenic variants in PALB2 are associated with increased risk of breast and pancreatic cancer. However, the functional and clinical relevance of many missense variants of uncertain significance (VUS) identified through clinical genetic testing is unclear. The ability of patient-derived germline missense VUS to disrupt PALB2 function was assessed to identify variants with potential clinical relevance.The influence of 84 VUS on PALB2 function was evaluated using a cellular homology directed DNA repair (HDR) assay and VUS impacting activity were further characterized using secondary functional assays.Four (~5%) variants (p.L24S,c.71T>C; p.L35P,c.104T>C; pI944N,c.2831T>A; and p.L1070P,c.3209T>C) disrupted PALB2-mediated HDR activity. These variants conferred sensitivity to cisplatin and a poly(ADP-ribose) polymerase (PARP) inhibitor and reduced RAD51 foci formation in response to DNA damage. The p.L24S and p.L35P variants disrupted BRCA1-PALB2 protein complexes, p.I944N was associated with protein instability, and both p.I944N and p.L1070P mislocalized PALB2 to the cytoplasm.These findings show that the HDR assay is an effective method for screening the influence of inherited variants on PALB2 function, that four missense variants impact PALB2 function and may influence cancer risk and response to therapy, and suggest that few inherited PALB2 missense variants disrupt PALB2 function in DNA repair.

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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 A1025T missense no effect PALB2 A1025T lies within WD repeat 4 of the palb2 protein (UniProt.org). A1025T results in homologous repair activity similar to wild-type Palb2 in culture (PMID: 31636395, PMID: 33964450), BRCA2-binding similar to wild-type in a mammalian two-hybrid assay, and rescues PARP inhibitor sensitivity in PALB2-null cells in culture (PMID: 31586400).
PALB2 C1060S missense unknown PALB2 C1060S lies within WD repeat 5 of the Palb2 protein (UniProt.org). C1060S does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 C77Vfs*100 frameshift loss of function - predicted PALB2 C77Vfs*100 indicates a shift in the reading frame starting at amino acid 77 and terminating 100 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). C77Vfs*100 results in indeterminate homology-directed DNA repair in cultured cells (PMID: 33964450), and due to the effects of other truncation mutations downstream of C77 (PMID: 33964450, PMID: 31636395, PMID: 31757951), is predicted to lead to a loss of Palb2 protein function.
PALB2 D595Mfs*4 frameshift loss of function - predicted PALB2 D595Mfs*4 indicates a shift in the reading frame starting at amino acid 595 and terminating four residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). D595Mfs*4 has not been characterized, however, due to the effects of other truncation mutations downstream of D595 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 D616H missense unknown PALB2 D616H does not lie within any known functional domains of the Palb2 protein (UniProt.org). D616H does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 D871G missense no effect - predicted PALB2 D871G lies within WD repeat 1 of the Palb2 protein (UniProt.org). D871G results in DNA damage-induced cell cycle checkpoint maintenance similar to wild-type (PMID: 31757951), and does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 E1010* nonsense loss of function - predicted PALB2 E1010* results in a premature truncation of the Palb2 protein at amino acid 1010 of 1186 (UniProt.org). E1010* has not been characterized however, due to the effects of other truncation mutations downstream of E1010 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 E1083D missense unknown PALB2 E1083D lies within WD repeat 5 of the Palb2 protein (UniProt.org). E1083D does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 E3* nonsense loss of function - predicted PALB2 E3* results in a premature truncation of the Palb2 protein at amino acid three of 1186 (UniProt.org). E3* has not been characterized however, due to the effects of other truncation mutations downstream of E3 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 E407* nonsense loss of function - predicted PALB2 E407* results in a premature truncation of the Palb2 protein at amino acid 407 of 1186 (UniProt.org). E407* has not been characterized, however, due to the effects of other truncation mutations downstream of E407 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 E672Q missense no effect PALB2 E672Q does not lie within any known functional domains of the Palb2 protein (UniProt.org). E672Q results in homology-directed DNA repair activity similar to wild-type Palb2 in a reporter assay (PMID: 33964450), and homology-directed DNA repair activity similar to wild-type in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951).
PALB2 F1181Lfs*54 frameshift loss of function - predicted PALB2 F1181Lfs*54 indicates a shift in the reading frame starting at amino acid 1181 and terminating 54 residues downstream, resulting in a premature truncation of the functional protein and extension of the 1186 amino acid Palb2 protein length by 49 amino acids (UniProt.org). F1181Lfs*54 has not been characterized, however, due to the effects of other truncation mutations downstream of F1181 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 F440fs frameshift loss of function - predicted PALB2 F440fs results in a change in the amino acid sequence of the Palb2 protein beginning at aa 440 of 1186, likely resulting in premature truncation of the functional protein (UniProt.org). F440fs has not been characterized however, due to the effects of other truncation mutations downstream of F440 (PMID: 31636395, PMID: 31757951), is predicted to lead to a loss of Palb2 protein function.
PALB2 G1043A missense loss of function - predicted PALB2 G1043A lies within WD repeat 4 of the Palb2 protein (UniProt.org). G1043A does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), however, results in decreased Brca2 binding, reduced Palb2 recruitment to DNA damage sites, and impaired homology-directed DNA repair activity in cultured cells in another study (PMID: 31586400), and therefore, is predicted to lead to a loss of Palb2 protein function.
PALB2 G1135E missense unknown PALB2 G1135E lies within WD repeat 6 of the Palb2 protein (UniProt.org). G1135E does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 G1174R missense unknown PALB2 G1174R lies within WD repeat 7 of the Palb2 protein (UniProt.org). G1174R does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 G808* nonsense loss of function - predicted PALB2 G808* results in a premature truncation of the Palb2 protein at amino acid 808 of 1186 (UniProt.org). G808* has not been characterized however, due to the effects of other truncation mutations downstream of G808 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 G866V missense unknown PALB2 G866V lies within WD repeat 1 of the Palb2 protein (UniProt.org). G866V does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 G998E missense no effect PALB2 G998E lies within WD repeat 3 of the Palb2 protein (UniProt.org). G998E results in Brca2 binding, Rad51 foci formation, and DNA damage-induced cell cycle checkpoint maintenance similar to wild-type Palb2 (PMID: 31586400, PMID: 31757951), and does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells (PMID: 31586400, PMID: 31636395, PMID: 31757951).
PALB2 I1093T missense no effect PALB2 I1093T lies within WD repeat 5 of the palb2 protein (UniProt.org). I1093T results in homologous repair activity similar to wild-type protein in culture (PMID: 31636395), demonstrates subcellular localization and recruitment to dsDNA damage sites comparable to wild-type Palb2 in culture, results in BRCA2 binding similar to wild-type protein in a mammalian two-hybrid assay, and rescues PARP inhibitor sensitivity in PALB2-null cells in culture (PMID: 31586400).
PALB2 I1180T missense no effect - predicted PALB2 I1180T lies within WD repeat 7 of the Palb2 protein (UniProt.org). I1180T results in Brca2 binding similar to wild-type Palb2 in cultured cells (PMID: 31586400), and does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 I309V missense no effect PALB2 I309V lies within the DNA-binding and BRCA1-interacting regions of the Palb2 protein (UniProt.org). I309V demonstrates homology-directed DNA repair activity similar to wild-type Palb2 in an in vitro assay (PMID: 33964450) and in cultured cells lacking Tp53 (PMID: 31636395).
PALB2 I944N missense loss of function PALB2 I944N lies within WD repeat 2 of the Palb2 protein (UniProt.org). I944N confers a loss of function to the Palb2 protein as demonstrated by decreased protein stability (PMID: 31757951), reduced Brca2 and Rad51 binding, recruitment to DNA damage sites, and Rad51 foci formation, aberrant cytosolic accumulation (PMID: 31636395), and loss of homology-directed DNA repair activity in cultured cells (PMID: 31636395, PMID: 31757951).
PALB2 K1048Rfs*27 frameshift loss of function - predicted PALB2 K1048Rfs*27 indicates a shift in the reading frame starting at amino acid 1048 and terminating 27 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). K1048Rfs*27 has not been characterized however, due to the effects of other truncation mutations downstream of K1048 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 K142Nfs*35 frameshift loss of function - predicted PALB2 K142Nfs*35 indicates a shift in the reading frame starting at amino acid 142 and terminating 35 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). K142Nfs*35 has not been characterized however, due to the effects of other truncation mutations downstream of K142 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 K25* nonsense loss of function - predicted PALB2 K25* results in a premature truncation of the Palb2 protein at amino acid 25 of 1186 (UniProt.org). K25* has not been characterized however, due to the effects of other truncation mutations downstream of K25 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 K346Tfs*13 frameshift loss of function - predicted PALB2 K346Tfs*13 indicates a shift in the reading frame starting at amino acid 346 and terminating 13 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). K346Tfs*13 has not been characterized, however, due to the effects of other Palb2 truncation mutations downstream of K346 (PMID: 31757951, PMID: 31636395), is predicted to lead to a loss of Palb2 protein function.
PALB2 K353Ifs*7 frameshift loss of function - predicted PALB2 K353Ifs*7 indicates a shift in the reading frame starting at amino acid 353 and terminating seven residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). K353Ifs*7 has not been characterized, however, due to the effects of other truncation mutations downstream of K353 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 K353Nfs*3 frameshift loss of function - predicted PALB2 K353Nfs*3 indicates a shift in the reading frame starting at amino acid 353 and terminating three residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). K353Nfs*3 has not been characterized, however, due to the effects of other truncation mutations downstream of K353 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 K515* nonsense loss of function - predicted PALB2 K515* results in a premature truncation of the Palb2 protein at amino acid 515 of 1186 (UniProt.org). K515* has not been characterized, however, due to the effects of other truncation mutations downstream of K515 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 K745E missense unknown PALB2 K745E does not lie within any known functional domains of the Palb2 protein (UniProt.org). K745E does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 K908fs frameshift loss of function - predicted PALB2 K908fs results in a change in the amino acid sequence of the Palb2 protein beginning at aa 908 of 1186, likely resulting in premature truncation of the functional protein (UniProt.org). K908fs has not been characterized however, due to the effects of other truncation mutations downstream of K908 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 L1070P missense loss of function PALB2 L1070P lies within WD repeat 5 of the Palb2 protein (UniProt.org). L1070P confers a loss of function to the Palb2 protein as demonstrated by decreased protein stability (PMID: 31757951), aberrant cytosolic accumulation and reduced Rad51 foci formation (PMID: 31636395), and intermediate or impaired homology-directed DNA repair activity compared to wild-type in cultured cells (PMID: 33964450, PMID: 31636395, PMID: 31757951).
PALB2 L1119P missense unknown PALB2 L1119P lies within WD repeat 6 of the Palb2 protein (UniProt.org). L1119P results in decreased nuclear localization, Brca2 binding, and recruitment to DNA damage sites and impaired homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells (PMID: 31586400), however, demonstrates similar Rad51 foci formation and increased Rad51 foci intensity to wild-type (PMID: 31586400), and does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951), and therefore, its effect on Palb2 protein function is unknown.
PALB2 L1143P missense unknown PALB2 L1143P lies within WD repeat 6 of the Palb2 protein (UniProt.org). The functional effect of L1143P is conflicting, as it has been reported to result in Brca2 binding similar to wild-type Palb2 in cultured cells (PMID: 31586400), and does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395), however, demonstrates decreased Rad51, Rad51c, and Xrcc3 binding in in vitro assays, and reduced Brca2 and Rad51c binding, decreased Rad51 foci formation, and impaired homology-directed DNA repair activity compared to wild-type in cultured cells (PMID: 24141787), and therefore, its effect on Palb2 protein function is unknown.
PALB2 L1150R missense unknown PALB2 L1150R lies within WD repeat 6 of the Palb2 protein (UniProt.org). L1150R does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 L169I missense unknown PALB2 L169I lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). L169I demonstrates subcellular localization and recruitment to laser-induced DNA damage sites similar to wild-type Palb2, results in deceased BRCA1 binding in a mammalian two-hybrid assay, reduced RAD51 foci formation and decreased homologous repair activity in one study (PMID: 31586400), but demonstrates homologous repair activity similar to wild-type Palb2 in another study (PMID: 31636395) and rescues PARP inhibitor sensitivity in PALB2-null cells in culture (PMID: 31586400), and therefore, its effect on Palb2 protein function is unknown.
PALB2 L24S missense loss of function PALB2 L24S lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). L24S confers a loss of function to the Palb2 protein as demonstrated by decreased Brca1 binding and Rad51 foci formation (PMID: 31636395), and impaired homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells (PMID: 31636395, PMID: 31757951, PMID: 33964450).
PALB2 L337S missense no effect - predicted PALB2 L337S lies within the DNA-binding region of the Palb2 protein (UniProt.org). L337S does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951), results in homologous recombination activity similar to wild-type protein in culture (PMID: 33169439), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 L659Qfs*3 frameshift loss of function - predicted PALB2 L659Qfs*3 indicates a shift in the reading frame starting at amino acid 659 and terminating three residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). L659Qfs*3 has not been characterized, however, due to the effects of other truncation mutations downstream of L659 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 L671* nonsense loss of function - predicted PALB2 L671* results in a premature truncation of the Palb2 protein at amino acid 671 of 1186 (UniProt.org). L671* has not been characterized, however, due to the effects of other truncation mutations downstream of L671 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 L931P missense unknown PALB2 L931P lies within WD repeat 2 of the Palb2 protein (UniProt.org). L931P does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 L931R missense no effect - predicted PALB2 L931R lies within WD repeat 2 of the Palb2 protein (UniProt.org). L931R results in DNA damage-induced cell cycle checkpoint maintenance similar to wild-type (PMID: 31757951), and does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 L936S missense unknown PALB2 L936S lies within WD repeat 2 of the Palb2 protein (UniProt.org). L936S does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on protein function is unknown.
PALB2 L939W missense unknown PALB2 L939W lies within WD repeat 2 of the Palb2 protein (UniProt.org). The functional effect of L939W is conflicting, as it has been reported to result in decreased Brca2, Rad51, and Xrcc3 binding in in vitro assays and a modest reduction in homology-directed DNA repair activity compared to wild-type in cultured cells (PMID: 24141787), but in another study demonstrates Brca2, Rad51, and Rad51c binding similar to wild-type Palb2 in cultured cells (PMID: 24141787, PMID: 31586400), and homology-directed DNA repair activity similar to wild-type in a reporter assay (PMID: 33964450), and in cultured cells lacking Tp53 (PMID: 27829436, PMID: 31636395, PMID: 31757951), and therefore, its effect on Palb2 protein function is unknown.
PALB2 L947F missense loss of function PALB2 L947F lies within WD repeat 2 of the Palb2 protein (UniProt.org). L947F results in reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells (PMID: 31586400, PMID: 31636395), Palb2 protein accumulation in the cytoplasm, and decreased Rad51 foci formation and foci intensity compared to wild-type protein (PMID: 31586400).
PALB2 L9H missense unknown PALB2 L9H lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). L9H does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 M296* nonsense loss of function - predicted PALB2 M296* results in a premature truncation of the Palb2 protein at amino acid 296 of 1186 (UniProt.org). M296* has not been characterized however, due to the effects of other truncation mutations downstream of M296 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 M723Vfs*21 frameshift loss of function - predicted PALB2 M723Vfs*21 indicates a shift in the reading frame starting at amino acid 723 and terminating 21 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). M723Vfs*21 has not been characterized, however, due to the effects of other truncation mutations downstream of M723 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 N280Tfs*8 frameshift loss of function - predicted PALB2 N280Tfs*8 indicates a shift in the reading frame starting at amino acid 280 and terminating 8 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). N280Tfs*8 has not been characterized however, due to the effects of other truncation mutations downstream of N280 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 N344Tfs*2 frameshift loss of function - predicted PALB2 N344Tfs*2 indicates a shift in the reading frame starting at amino acid 344 and terminating two residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). N344Tfs*2 has not been characterized, however, due to the effects of other Palb2 truncation mutations downstream of N344 (PMID: 31757951, PMID: 31636395), is predicted to lead to a loss of Palb2 protein function.
PALB2 N716K missense unknown PALB2 N716K does not lie within any known functional domains of the Palb2 protein (UniProt.org). N716K does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 N821Tfs*25 frameshift loss of function - predicted PALB2 N821Tfs*25 indicates a shift in the reading frame starting at amino acid 821 and terminating 25 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). N821Tfs*25 has not been characterized however, due to the effects of other truncation mutations downstream of N821 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 P113Qfs*64 frameshift loss of function - predicted PALB2 P113Qfs*64 indicates a shift in the reading frame starting at amino acid 113 and terminating 64 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). P113Qfs*64 has not been characterized however, due to the effects of other truncation mutations downstream of P113 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 P210L missense no effect PALB2 P210L lies within the DNA-binding and BRCA1-interacting regions of the Palb2 protein (UniProt.org). P210L retains homology-directed DNA repair activity in cultured cells (PMID: 31636395, PMID: 31757951), results in BRCA1 binding similar to wild-type Palb2 in a mammalian two-hybrid assay, and rescues PARP inhibitor sensitivity in PALB2-null cells in culture (PMID: 31586400)
PALB2 P378Lfs*46 frameshift loss of function - predicted PALB2 P378Lfs*46 indicates a shift in the reading frame starting at amino acid 378 and terminating 46 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). P378Lfs*46 has not been characterized, however, due to the effects of other truncation mutations downstream of P378 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 P864S missense no effect PALB2 P864S lies within WD repeat 1 of the Palb2 protein (UniProt.org). P864S results in Brca2 binding, Rad51 foci formation, and recruitment to DNA damage sites similar to wild-type Palb2 in cultured cells (PMID: 31586400), retains homology-directed DNA repair activity in cultured cells (PMID: 31586400, PMID: 31636395, PMID: 31757951), and rescues PARP inhibitor sensitivity in PALB2-null cells (PMID: 31586400).
PALB2 P8L missense unknown PALB2 P8L lies within the DNA-binding and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). P8L demonstrates subcellular localization, recruitment to DNA damage sites, and Brca1 binding similar to wild-type Palb2 (PMID: 31586400), and leads to homology-directed DNA repair activity similar to wild-type Palb2 in one study (PMID: 31636395), but results in impaired homology-directed DNA repair activity, reduced Rad51 foci formation, and fails to rescue PARP inhibitor sensitivity in PALB2-null cells in another study (PMID: 31586400), and therefore, its effect on Palb2 protein function is unknown.
PALB2 Q1023* nonsense loss of function - predicted PALB2 Q1023* results in a premature truncation of the Palb2 protein at amino acid 1023 of 1186 (UniProt.org). Q1023* has not been characterized however, due to the effects of other truncation mutations downstream of Q1023 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 Q1056* nonsense loss of function - predicted PALB2 Q1056* results in a premature truncation of the Palb2 protein at amino acid 1056 of 1186 (UniProt.org). Q1056* has not been characterized, however, due to the effects of other truncation mutations downstream of Q1056 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 Q1114H missense no effect - predicted PALB2 Q1114H lies within the RAD51, BRCA2, and POLH-interacting region of the Palb2 protein (UniProt.org). Q1114H results in Brca2 binding similar to wild-type Palb2 in cultured cells (PMID: 31586400), and does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), and therefore, is predicted to have no effect on protein function.
PALB2 Q251* nonsense loss of function - predicted PALB2 Q251* results in a premature truncation of the Palb2 protein at amino acid 251 of 1186 (UniProt.org). Q251* results in impaired homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395), and therefore, is predicted to lead to a loss of Palb2 protein function.
PALB2 Q348* nonsense loss of function - predicted PALB2 Q348* results in a premature truncation of the Palb2 protein at amino acid 348 of 1186 (UniProt.org). Q348* has not been characterized, however, due to the effects of other truncation mutations downstream of Q348 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 Q559R missense no effect PALB2 Q559R lies within the DNA-binding region of the Palb2 protein (UniProt.org). Q559R is a common Palb2 polymorphism (PMID: 23977390, PMID: 21165770), results in homologous recombination similar to wild-type Palb2 (PMID: 33169439, PMID: 33964450) and does not demonstrate reduced homology-directed DNA repair activity in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951).
PALB2 Q790* nonsense loss of function - predicted PALB2 Q790* results in a premature truncation of the Palb2 protein at amino acid 790 of 1186 (UniProt.org). Q790* has not been characterized, however, due to the effects of other truncation mutations downstream of Q790 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 Q921Tfs*7 frameshift loss of function - predicted PALB2 Q921Tfs*7 indicates a shift in the reading frame starting at amino acid 921 and terminating seven residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). Q921Tfs*7 has not been characterized however, due to the effects of other truncation mutations downstream of Q921 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 Q958P missense unknown PALB2 Q958P lies within WD repeat 2 of the Palb2 protein (UniProt.org). Q958P does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 R1086Efs*9 frameshift loss of function - predicted PALB2 R1086Efs*9 indicates a shift in the reading frame starting at amino acid 1086 and terminating 9 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). R1086Efs*9 has not been characterized, however, due to the effects of other truncation mutations downstream of R1086 (PMID: 31757951, PMID: 31636395), is predicted to result in a loss of Palb2 protein function.
PALB2 R131fs frameshift loss of function - predicted PALB2 R131fs results in a change in the amino acid sequence of the Palb2 protein beginning at aa 131 of 1186, likely resulting in premature truncation of the functional protein (UniProt.org). R131fs has not been characterized however, due to the effects of other truncation mutations downstream of R131 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 R34C missense unknown PALB2 R34C lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). R34C does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 R34H missense unknown PALB2 R34H lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). R34H does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 R37C missense unknown PALB2 R37C lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). R37C demonstrates homology-directed DNA repair activity similar to wild-type in cultured cells in one study (PMID: 31636395), but results in decreased homology-directed DNA repair activity in another study (PMID: 33811135), and therefore, its effect on Palb2 protein function is unknown.
PALB2 R37S missense no effect - predicted PALB2 R37S lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). R37S results in homology-directed DNA repair similar to wild-type Palb2 in cultured cells (PMID: 31636395, PMID: 33964450), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 R414* nonsense loss of function - predicted PALB2 R414* results in a premature truncation of the Palb2 protein at amino acid 414 of 1186 (UniProt.org). R414* has not been characterized however, due to the effects of other truncation mutations downstream of R414 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 S1102R missense unknown PALB2 S1102R lies within WD repeat 5 of the Palb2 protein (UniProt.org). S1102R does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 S1165L missense unknown PALB2 S1165L lies within WD repeat 7 of the Palb2 protein (UniProt.org). S1165L does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on protein function is unknown.
PALB2 S382I missense unknown PALB2 S382I lies within the DNA-binding region of the Palb2 protein (UniProt.org). S382I does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 S387Lfs*14 frameshift loss of function - predicted PALB2 S387Lfs*14 indicates a shift in the reading frame starting at amino acid 387 and terminating 14 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). S387Lfs*14 has not been characterized, however, due to the effects of other truncation mutations downstream of S387 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 S417Y missense no effect - predicted PALB2 S417Y lies within the DNA-binding and chromatin-association motif regions of the Palb2 protein (UniProt.org). S417Y results in reduced chromatin interaction compared to wild-type Palb2 (PMID: 29387807), however, demonstrates Rad51 foci formation and cell survival in response to genotoxic stress similar to wild-type in cultured cells (PMID: 29387807), and does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 S474N missense unknown PALB2 S474N lies within the DNA-binding region of the Palb2 protein (UniProt.org). S474N does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 S578G missense unknown PALB2 S578G lies within the DNA-binding region of the Palb2 protein (UniProt.org). S578G does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 S779* nonsense loss of function - predicted PALB2 S779* results in a premature truncation of the Palb2 protein at amino acid 779 of 1186 (UniProt.org). S779* has not been characterized, however, due to the effects of other truncation mutations downstream of S779 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 S859* nonsense loss of function - predicted PALB2 S859* results in a premature truncation of the Palb2 protein at amino acid 859 of 1186 (UniProt.org). S859* has not been characterized however, due to the effects of other truncation mutations downstream of S859 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 S951F missense unknown PALB2 S951F lies within WD repeat 2 of the Palb2 protein (UniProt.org). S951F does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on protein function is unknown.
PALB2 S979Vfs*11 frameshift loss of function - predicted PALB2 S979Vfs*11 indicates a shift in the reading frame starting at amino acid 979 and terminating 11 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). S979Vfs*11 has not been characterized however, due to the effects of other truncation mutations downstream of S979 (PMID: 31757951, PMID: 31636395), is predicted to result in a loss of Palb2 protein function.
PALB2 T1030I missense loss of function PALB2 T1030I lies within WD repeat 4 of the Palb2 protein (UniProt.org). T1030I confers a loss of function to the Palb2 protein as demonstrated by reduced Rad51 and Rad51c binding in in vitro assays (PMID: 24141787), decreased protein stability (PMID: 24141787, PMID: 31757951), reduced Rad51 foci formation, loss of Brca2 binding, and aberrant cytoplasmic localization (PMID: 31586400), and impaired homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells (PMID: 31586400, PMID: 31636395, PMID: 31757951).
PALB2 T1099R missense unknown PALB2 T1099R lies within WD repeat 5 of the Palb2 protein (UniProt.org). T1099R does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 T1167I missense unknown PALB2 T1167I lies within WD repeat 7 of the Palb2 protein (UniProt.org). T1167I does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 T351Rfs*4 frameshift loss of function - predicted PALB2 T351Rfs*4 indicates a shift in the reading frame starting at amino acid 351 and terminating four residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). T351Rfs*4 has not been characterized, however, due to the effects of other truncation mutations downstream of T351 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 T397I missense unknown PALB2 T397I lies within the DNA-binding and chromatin-association motif regions of the Palb2 protein (UniProt.org). T397I does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 T397S missense unknown PALB2 T397S lies within the DNA-binding and chromatin-association motif regions of the Palb2 protein (UniProt.org). T397S does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395) and demonstrates chromatin association similar to wild-type Palb2 in cell culture (PMID: 29387807), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 T413Hfs*11 frameshift loss of function - predicted PALB2 T413Hfs*11 indicates a shift in the reading frame starting at amino acid 413 and terminating 11 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). T413Hfs*11 has not been characterized however, due to the effects of other truncation mutations downstream of T413 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 T413K missense unknown PALB2 T413K lies within the DNA-binding and chromatin-association motif regions of the Palb2 protein (UniProt.org). T413K does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 T494Lfs*67 frameshift loss of function - predicted PALB2 T494Lfs*67 indicates a shift in the reading frame starting at amino acid 494 and terminating 67 residues downstream causing a premature truncation of the 1186 amino acid Palb2 protein (UniProt.org). T494Lfs*67 has not been characterized, however, due to the effects of other Palb2 truncation mutations downstream of T494 (PMID: 31757951, PMID: 31636395), is predicted to lead to a loss of Palb2 protein function.
PALB2 T734S missense unknown PALB2 T734S does not lie within any known functional domains of the Palb2 protein (UniProt.org). T734S does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 V1019A missense unknown PALB2 V1019A lies within WD repeat 4 of the Palb2 protein (UniProt.org). V1019A does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 V1103L missense unknown PALB2 V1103L lies within WD repeat 5 of the Palb2 protein (UniProt.org). V1103L does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 V1103M missense unknown PALB2 V1103M lies within WD repeat 5 of the Palb2 protein (UniProt.org). V1103M does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 V78I missense no effect PALB2 V78I lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). V78I demonstrates homology-directed DNA repair activity comparable to wild-type Palb2 in culture (PMID: 31636395), and results in BRCA2-binding similar to wild-type Palb2 in a mammalian two-hybrid assay and rescues PARP inhibitor sensitivity in PALB2-null cells in culture (PMID: 31586400).
PALB2 V932M missense no effect PALB2 V932M lies within WD repeat 2 of the Palb2 protein (UniProt.org). V932M results in Brca2 binding, Rad51 foci formation, and recruitment to DNA damage sites similar to wild-type Palb2 in cultured cells (PMID: 31586400), and does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells (PMID: 31586400, PMID: 31636395, PMID: 33964450).
PALB2 W1140G missense loss of function - predicted PALB2 W1140G lies within WD repeat 6 of the Palb2 protein (UniProt.org). W1140G does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395), however, results in decreased Brca2 binding, reduced Rad51 foci formation, aberrant cytoplasmic localization, and impaired homology-directed DNA repair activity compared to wild-type in cultured cells (PMID: 31586400), and therefore, is predicted to lead to a loss of Palb2 protein function.
PALB2 W1164C missense unknown PALB2 W1164C lies within WD repeat 7 of the Palb2 protein (UniProt.org). W1164C does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 W898* nonsense loss of function - predicted PALB2 W898* results in a premature truncation of the Palb2 protein at amino acid 898 of 1186 (UniProt.org). W898* has not been characterized however, due to the effects of other truncation mutations downstream of W898 (PMID: 31636395, PMID: 31757951), is predicted to result in a loss of Palb2 protein function.
PALB2 Y1064C missense no effect - predicted PALB2 Y1064C lies within WD repeat 5 of the Palb2 protein (UniProt.org). Y1064C results in DNA damage-induced cell cycle checkpoint maintenance similar to wild-type (PMID: 31757951), and does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 Y1108fs frameshift loss of function - predicted PALB2 Y1108fs results in a change in the amino acid sequence of the Palb2 protein beginning at aa 1108 of 1186, likely resulting in premature truncation of the functional protein (UniProt.org). Y1108fs results in impaired homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395), and therefore, is predicted to lead to a loss of protein function.
PALB2 Y1183* nonsense loss of function PALB2 Y1183* results in a premature truncation of the Palb2 protein at amino acid 1183 of 1186 (UniProt.org). Y1183* confers a loss of function to the Palb2 protein as demonstrated by decreased protein stability (PMID: 31757951), and impaired homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951).
PALB2 Y408H missense no effect - predicted PALB2 Y408H lies within the DNA-binding and chromatin-association motif regions of the Palb2 protein (UniProt.org). Y408H results in DNA damage-induced cell cycle checkpoint maintenance similar to wild-type (PMID: 31757951), and does not demonstrate reduced homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 Y551* nonsense loss of function PALB2 Y551* results in a premature truncation of the Palb2 protein at amino acid 551 of 1186 (UniProt.org). Y551* confers a loss of function to the Palb2 protein as demonstrated by loss of Brca2 and Rad51c binding and reduced Rad51 binding in cultured cells (PMID: 24141787), and impaired homology-directed DNA repair activity compared to wild-type in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PALB2 L1070P Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, cells expressing PALB2 L1070P were sensitive to treatment with Lynparza (olaparib) in culture, demonstrating decreased cell survival (PMID: 31636395). 31636395
PALB2 I944N Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, cells expressing PALB2 I944N were sensitive to treatment with Lynparza (olaparib) in culture, demonstrating decreased cell survival (PMID: 31636395). 31636395
PALB2 L35P Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, cells expressing PALB2 L35P were sensitive to treatment with Lynparza (olaparib) in culture, demonstrating decreased cell survival (PMID: 31636395). 31636395
PALB2 A1025R Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, cells expressing PALB2 A1025R were sensitive to treatment with Lynparza (olaparib) in culture, demonstrating decreased cell survival (PMID: 31636395). 31636395
PALB2 L24S Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, cells expressing PALB2 L24S were sensitive to treatment with Lynparza (olaparib) in culture, demonstrating decreased cell survival (PMID: 31636395). 31636395