Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Tischkowitz, Marc; Balmañà, Judith; Foulkes, William D.; James, Paul; Ngeow, Joanne; Schmutzler, Rita K.; Voian, Nicoleta C.; Wick, Myra J.; Stewart, Douglas R.; Pal, Tuya

doi:10.1038/s41436-021-01151-8

Cited by 43 publications

(55 citation statements)

References 61 publications

(84 reference statements)

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“…There is strong evidence that (likely) pathogenic PALB2 variants confer breast cancer risks that are considered as moderate to high. Therefore, multidisciplinary committees should advise a close surveillance and discuss the indication of a contralateral prophylactic mastectomy in these patients [ 25 ]. Finally, our patient was treated with a total mastectomy of the right breast followed by chemotherapy, adjuvant radiotherapy, and hormone therapy ( Tamoxifen ).…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of an Exonic Duplication in PALB2 in a Man with Synchronous Breast and Prostate Cancer

Bouras

Lafaye

Léoné

et al. 2022

IJMS

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PALB2 (partner and localizer of BRCA2), as indicated by its name, is a BRCA2-interacting protein that plays an important role in homologous recombination (HR) and DNA double-strand break (DSB) repair. While pathogenic variants of PALB2 have been well proven to confer an increased risk of breast cancer, data on its involvement in prostate cancer (PrC) have not been clearly demonstrated. We investigated, using targeted next generation sequencing (NGS), a 59-year-old Caucasian man who developed synchronous breast and prostate cancers. This genetic investigation allowed to identify an intragenic germline heterozygous duplication in PALB2, implicating intronic repetitive sequences spanning exon 11. This variant was confirmed by multiplex ligation probe amplification (MLPA), and genomic breakpoints have been identified and characterized at the nucleotide level (c.3114-811_3202-1756dup) using an approach based on walking PCR, long range PCR, and Sanger sequencing. RT-PCR using mRNA extracted from lymphocytes and followed by Sanger sequencing revealed a tandem duplication r.3114_3201dup; p.(Gly1068Glufs * 14). This duplication results in the synthesis of a truncated, and most-likely, non-functional protein. These findings expand the phenotypic spectrum of PALB2 variants and may improve the yield of genetic diagnoses in this field.

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of an Exonic Duplication in PALB2 in a Man with Synchronous Breast and Prostate Cancer

Bouras

Lafaye

Léoné

et al. 2022

IJMS

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“…The American College of Medical Genetics and Genomics (ACMG) recommends that PALB2 gene testing should be included in the test panel for breast, ovarian, and pancreatic cancer. In addition, patients with PALB2 mutation should be offered breast cancer surveillance similar to that for BRCA1/2 carriers [50]. Currently, there is no standardized therapy for PALB2 mutation associated breast cancer due to the limited amount of evidence available; however, some clinical trials have proved the use of PARP inhibitors as beneficial.…”

Section: Discussionmentioning

confidence: 99%

Germline PALB2 Mutation in High-Risk Chinese Breast and/or Ovarian Cancer Patients

Kwong

Shin

et al. 2021

Cancers

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The prevalence of the PALB2 mutation in breast cancer varies across different ethnic groups; hence, it is of intense interest to evaluate the cancer risk and clinical association of the PALB2 mutation in Chinese breast and/or ovarian cancer patients. We performed sequencing with a 6-gene test panel (BRCA1, BRCA2, TP53, PTEN, PALB2, and CDH1) to identify the prevalence of the PALB2 germline mutation among 2631 patients with breast and/or ovarian cancer. In this cohort, 39 mutations were identified with 24 types of mutation variants, where the majority of the mutations were frame-shift mutations and resulted in early termination. We also identified seven novel PALB2 mutations. Most of the PALB2 mutation carriers had breast cancer (36, 92.3%) and were more likely to have family history of breast cancer (19, 48.7%). The majority of the breast tumors were invasive ductal carcinoma (NOS type) (34, 81.0%) and hormonal positive (ER: 32, 84.2%; PR: 23, 60.5%). Pathogenic mutations of PALB2 were found in 39 probands with a mutation frequency of 1.6% and 1% in breast cancer and ovarian cancer patients, respectively. PALB2 mutation carriers were more likely have hormonal positive tumors and were likely to have familial aggregation of breast cancer.

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“…PALB2 pathogenic germline variants are associated with a 7.18, 2.91, and 2.37 RR of developing female breast, ovarian, and pancreatic cancer, respectively, and their estimated incidence up to age 80 years is 53%, 5%, and 2%-3%, respectively [17]. The latest American College of Medical Genetics and Genomics guidelines recommend that pancreatic cancer surveillance should be considered for germline PALB2 pathogenic variant [18].…”

Section: Palb2mentioning

confidence: 99%

Hereditary pancreatic cancer

et al. 2021

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Pancreatic cancer is associated with both family and hereditary cancer syndromes. Multigene panel testing for pancreatic cancer detected the germline variants BRCA1/2, PALB2, ATM, TP53, MLH1, STK11/LKB1, APC, CDKN2A, and SPINK1/PRSS1 as high-risk genes. A latest genome-wide association study revealed the common, but low-risk germline variants in pancreatic cancer patients. Active pancreatic surveillance using magnetic resonance imaging and endoscopic ultrasound is recommended for high-risk individuals who have a family history of pancreatic cancer or harbor these germline pathogenic variants to improve the detection rate and prognosis of pancreatic cancer. Since poly-ADP-ribose polymerase (PARP) inhibitor has been shown to be effective in improving the prognosis of BRCA-positive pancreatic cancer as well as hereditary breast and ovarian cancer syndrome, PARP inhibitor therapy is currently being applied as precision medicine to pancreatic cancer patients harboring the BRCA1/2 germline variant. This review highlights the importance of surveillance for germline pathogenic variants in pancreatic cancer and is expected to lead to improvements in the diagnosis and prevention of pancreatic cancer as well as facilitate the development of effective therapeutic strategies and precision medicine.

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Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Cited by 43 publications

References 61 publications

Identification and Characterization of an Exonic Duplication in PALB2 in a Man with Synchronous Breast and Prostate Cancer

Identification and Characterization of an Exonic Duplication in PALB2 in a Man with Synchronous Breast and Prostate Cancer

Germline PALB2 Mutation in High-Risk Chinese Breast and/or Ovarian Cancer Patients

Hereditary pancreatic cancer

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