The PALB2 p.Leu939Trp mutation is not associated with breast cancer risk

Catucci, Irene; Radice, Paolo; Milne, Roger L.; Couch, Fergus J.; Southey, Melissa C.; Peterlongo, Paolo

doi:10.1186/s13058-016-0762-9

Cited by 10 publications

(8 citation statements)

References 5 publications

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“…A first study showed that this variant falls in the PALB2 WD40 domain and results in altered PALB2‐BRCA2 binding . However, it was then demonstrated that it does not disrupt the HR‐mediated DNA repair activity of PALB2 . Two case–control studies conducted in the German population and in the British population on over 800 and 923 familial BC cases, respectively, showed that the c.2816T>G variant was not associated with BC.…”

Section: Discussionmentioning

confidence: 99%

“…51 However, it was then demonstrated that it does not disrupt the HR-mediated DNA repair activity of PALB2. 52 Two case-control studies conducted in the German population 53 and in the British population 6 on over 800 and 923 familial BC cases, respectively, showed that the c.2816T>G variant was not associated with BC. More recently, a multicenter casecontrol study conducted by the Breast Cancer Association Consortium (BCAC) on 42,671 invasive BC and 42,164 controls did not show any association with this variant (OR c.2816T>G = 1.05; 95%CI 0.83-1.32), 49 leading to the conclusion that the PALB2 c.2816T>G variant should be classified as a likely neutral variant.…”

Section: Discussionmentioning

confidence: 99%

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Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Girard

Eon-Marchais

Olaso

et al. 2018

Intl Journal of Cancer

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Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost‐effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of our study was to assess the contribution of rare, deleterious‐predicted variants in DNA repair genes in familial breast cancer (BC) in a well‐characterized and homogeneous population. We analyzed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC ( N = 1,207), and general population controls ( N = 1,199). Sequencing data were filtered for rare loss‐of‐function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2 , ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI , MAST1 , POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (OR LoF = 17.4 vs. OR MV = 1.6; p Het = 0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious‐predicted variants in PALB2 , ATM and CHEK2 and to add MAST1 , POLH , RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Girard

Eon-Marchais

Olaso

et al. 2018

Intl Journal of Cancer

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“…Park and colleagues reported that the PALB2 :p.Leu939Trp variant might be pathogenic based on the fact that it resulted in altered BRCA2-PALB2 binding, decreased HR capacity, and increased sensitivity to ionizing radiation ( 28 ). However, we provided strong evidences deriving from additional functional studies and very large case-control studies that the PALB2 :p.Leu939Trp is a neutral variant ( 23 ). As a final consideration, it should be noted that of the many missense variants that were functionally proved to prevent the BRCA1-PALB2-BRCA2 complex formation ( 16 , 19 , 24 ), all, with the only exception of the PALB2 :p.Leu939Trp that is consider benign or likely benign, are annotated or should be treated clinically as VUS.…”

Section: Discussionmentioning

confidence: 84%

“…Six BRCA2 or PALB2 variants located in the protein interaction domain were included as positive and negative controls. The PALB2 :c.2816T>G (p.Leu939Trp) variant was reported to be not associated with breast cancer risk and to not alter the protein DNA repair activity by HR ( 22 , 23 ). The BRCA2 :c.79A>G (p.Ile27Val) and PALB2 :c.3064AT>GC (p.Met1022Ala) missense variants were functionally tested and resulted not disrupting the BRCA2-PALB2 interaction ( 16 , 24 ).…”

Section: Methodsmentioning

confidence: 99%

Two Missense Variants Detected in Breast Cancer Probands Preventing BRCA2-PALB2 Protein Interaction

et al. 2018

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PALB2 (partner and localizer of BRCA2) was initially identified as a binding partner of BRCA2. It interacts also with BRCA1 forming a complex promoting DNA repair by homologous recombination. Germline pathogenic variants in BRCA1, BRCA2 and PALB2 DNA repair genes are associated with high risk of developing breast cancer. Mutation screening in these breast cancer predisposition genes is routinely performed and allows the identification of individuals who carry pathogenic variants and are at risk of developing the disease. However, variants of uncertain significance (VUSs) are often detected and establishing their pathogenicity and clinical relevance remains a central challenge for the risk assessment of the carriers and the clinical decision-making process. Many of these VUSs are missense variants leading to single amino acid substitutions, whose impact on protein function is uncertain. Typically, VUSs are rare and due to the limited genetic, clinical, and pathological data the multifactorial approaches used for classification cannot be applied. Thus, these variants can only be characterized through functional analyses comparing their effect with that of normal and mutant gene products used as positive and negative controls. The two missense variants BRCA2:c.91T >G (p.Trp31Gly) and PALB2:c.3262C >T (p.Pro1088Ser) were detected in two breast cancer probands originally ascertained at Breast Cancer Units of Institutes located in Milan and Bergamo (Northern Italy), respectively. These variants were located in the BRCA2-PALB2 interacting domains, were predicted to be deleterious by in silico analyses, and were very rare and clinically not classified. Therefore, we initiate to study their functional effect by exploiting a green fluorescent protein (GFP)-reassembly in vitro assay specifically designed to test the BRCA2-PALB2 interaction. This functional assay proved to be easy to develop, robust and reliable. It also allows testing variants located in different genes. Results from these functional analyses showed that the BRCA2:p.Trp31Gly and the PALB2:p.Pro1088Ser prevented the BRCA2-PALB2 binding. While caution is warranted when the interpretation of the clinical significance of rare VUSs is based on functional studies only, our data provide initial evidences in favor of the possibility that these variants are pathogenic.

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“…L939W is listed as having conflicting interpretations in ClinVar, with a combination of likely benign, benign, and VUS classifications reported from different clinical laboratories. There are previous reports that L939W displays a modest decrease in BRCA2 and RAD51 binding, and affects HR capacity 36 , but others have been unable to reproduce this HR finding 23,25,54 . Given that the original studies of abnormal activity were conducted without validation controls, these results do not qualify as strong PS3 evidence and should be interpreted cautiously in light of substantial refuting evidence.…”

Section: Palb2 Residues V1019 M1022 A1025 I1037 L1046 K1047 L10mentioning

confidence: 89%

A Validated Functional Analysis of PALB2 Missense Variants for Use in Clinical Variant Interpretation

Brnich¹,

Arteaga²,

Tan³

et al. 2020

Preprint

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Clinical genetic testing readily detects germline genetic variants. Yet, the evidence available for variant classification as benign or pathogenic is often limited by the rarity of individual variants, leading to many “variant of uncertain significance” (VUS) classifications. VUS cannot guide clinical decisions, complicating counseling and management. Laboratory assays can potentially aid reclassification, but require benchmarking against variants with definitive interpretations to have sufficient predictive power for clinical use. Of all clinically identified germline variants in hereditary breast cancer gene PALB2 (Partner and Localizer of BRCA2), ~50% are VUS and ~90% of VUS are missense. Truncating PALB2 variants have homologous recombination (HR) defects and instead rely on error-prone non-homologous end-joining (NHEJ) for DNA damage repair (DDR). Recent reports show some missense PALB2 variants may also be damaging, but thus far functional studies have lacked benchmarking controls. Using the Traffic Light Reporter (TLR) to quantify cellular HR and NHEJ using fluorescent markers, we assessed variant-level DDR capacity in hereditary breast cancer genes. We first determined the TLR’s dynamic range using BRCA2 missense variants of known significance as benchmarks for normal/abnormal HR function. We then tested 37 PALB2 variants, generating functional data for germline PALB2 variants at a moderate level of evidence for a pathogenic interpretation (PS3_moderate) for 8 variants, or a supporting level of evidence in favor of a benign interpretation (BS3_supporting) for 13 variants, based on the ability of the assay to correctly classify PALB2 validation controls. This new data can be applied in subsequent variant interpretations for direct clinical benefit.

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The PALB2 p.Leu939Trp mutation is not associated with breast cancer risk

Cited by 10 publications

References 5 publications

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Two Missense Variants Detected in Breast Cancer Probands Preventing BRCA2-PALB2 Protein Interaction

A Validated Functional Analysis of PALB2 Missense Variants for Use in Clinical Variant Interpretation

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