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Ref Type Journal Article
PMID (33811135)
Authors Ng PS, Boonen RA, Wijaya E, Chong CE, Sharma M, Knaup S, Mariapun S, Ho WK, Lim J, Yoon SY, Mohd Taib NA, See MH, Li J, Lim SH, Tan EY, Tan BK, Tan SM, Tan VK, van Dam RM, Rahmat K, Yip CH, Carvalho S, Luccarini C, Baynes C, Dunning AM, Antoniou A, van Attikum H, Easton DF, Hartman M, Teo SH
Title Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore.
Journal Journal of medical genetics
Vol
Issue
Date 2021 Apr 02
URL
Abstract Text Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population.Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays.PTVs in PALB2 were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p<0.0001). In contrast, rare missense variants in PALB2 were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in PALB2. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks.Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.

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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 A38G missense unknown PALB2 A38G lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). A38G demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 A38V missense unknown PALB2 A38V lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). A38V demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 C419R missense unknown PALB2 C419R lies within the DNA-binding and chromatin-association motif regions of the Palb2 protein (UniProt.org). C419R demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 G1043V missense loss of function PALB2 G1043V lies within WD repeat 4 of the Palb2 protein (UniProt.org). G1043V results in decreased Palb2 protein stability, loss of nuclear localization, impaired homology-directed DNA repair activity in cultured cells, and confers sensitivity to PARP inhibition in PALB2-deficient cells (PMID: 33811135).
PALB2 G401R missense unknown PALB2 G401R lies within the DNA-binding and chromatin-association motif regions of the Palb2 protein (UniProt.org). G401R demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 H1184L missense unknown PALB2 H1184L lies within WD repeat 7 of the Palb2 protein (UniProt.org). H1184L demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 L1027R missense loss of function PALB2 L1027R lies within WD repeat 4 of the Palb2 protein (UniProt.org). L1027R results in decreased Palb2 protein stability, loss of nuclear localization, impaired homology-directed DNA repair activity in cultured cells, and confers sensitivity to PARP inhibition in PALB2-deficient cells (PMID: 33811135).
PALB2 L9V missense unknown PALB2 L9V lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). L9V demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 P405A missense unknown 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 in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 P615S missense unknown PALB2 P615S does not lie within any known functional domains of the Palb2 protein (UniProt.org). P615S demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 Q1044H missense unknown PALB2 Q1044H lies within WD repeat 4 of the Palb2 protein (UniProt.org). Q1044H demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 Q39L missense unknown PALB2 Q39L lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). Q39L demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), 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 S1169C missense unknown PALB2 S1169C lies within WD repeat 7 of the Palb2 protein (UniProt.org). S1169C demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 S896F missense unknown PALB2 S896F lies within WD repeat 1 of the Palb2 protein (UniProt.org). S896F demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 T1012I missense unknown PALB2 T1012I lies within WD repeat 4 of the Palb2 protein (UniProt.org). T1012I demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 T993M missense unknown PALB2 T993M lies within WD repeat 3 of the Palb2 protein (UniProt.org). T993M demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 V1036A missense unknown PALB2 V1036A lies within WD repeat 4 of the Palb2 protein (UniProt.org). V1036A demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
PALB2 Y409C missense unknown PALB2 Y409C lies within the DNA-binding and chromatin-association motif regions of the Palb2 protein (UniProt.org). Y409C demonstrates homology-directed DNA repair activity in cultured cells (PMID: 33811135), but has not been fully biochemically characterized and therefore, its effect on Palb2 protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PALB2 A38V Advanced Solid Tumor no benefit Olaparib Preclinical - Cell culture Actionable In a preclinical study, expressing PALB2 A38V did not confer sensitivity to Lynparza (olaparib)-induced growth inhibition in TP53 and PALB2 double knock-out mouse embryonic stem cells in culture (PMID: 33811135). 33811135
PALB2 G1043V Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, expressing PALB2 G1043V conferred sensitivity to Lynparza (olaparib)-induced growth inhibition in TP53 and PALB2 double knock-out mouse embryonic stem cells in culture (PMID: 33811135). 33811135
PALB2 L1027R Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, expressing PALB2 L1027R conferred sensitivity to Lynparza (olaparib)-induced growth inhibition in TP53 and PALB2 double knock-out mouse embryonic stem cells in culture (PMID: 33811135). 33811135
PALB2 R37H Advanced Solid Tumor conflicting Olaparib Preclinical - Cell culture Actionable In a preclinical study, expressing PALB2 R37H did not confer sensitivity to Lynparza (olaparib)-induced growth inhibition in TP53 and PALB2 double knock-out mouse embryonic stem cells in culture (PMID: 33811135). 33811135