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2. Genome-first approach of the prevalence and cancer phenotypes of pathogenic or likely pathogenic germline TP53 variants

Author

de Andrade, Kelvin C., Strande, Natasha T., Kim, Jung, Haley, Jeremy S., Hatton, Jessica N., Frone, Megan N., Khincha, Payal P., Thone, Gretchen M., Mirshahi, Uyenlinh L., Schneider, Cynthia, Desai, Heena, Dove, James T., Smelser, Diane T., Levine, Arnold J., Maxwell, Kara N., Stewart, Douglas R., Carey, David J., and Savage, Sharon A.

Published
2024
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4. Genome-First Approach of the Prevalence and Cancer Phenotypes of Pathogenic or Likely Pathogenic Germline TP53 Variants

Author

de Andrade, Kelvin C., primary, Strande, Natasha T., additional, Kim, Jung, additional, Haley, Jeremy S., additional, Hatton, Jessica N., additional, Frone, Megan N., additional, Khincha, Payal P., additional, Thone, Gretchen M., additional, Mirshahi, Uyenlinh L., additional, Schneider, Cynthia, additional, Desai, Heena, additional, Dove, James T., additional, Smelser, Diane T., additional, BioBank, Penn Medicine, additional, Center, Regeneron Genetics, additional, Levine, Arnold J., additional, Maxwell, Kara N., additional, Stewart, Douglas R., additional, Carey, David J., additional, and Savage, Sharon A., additional

Published
2023
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6. Supplementary Data S3 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Author

Subasri, Vallijah, primary, Light, Nicholas, primary, Kanwar, Nisha, primary, Brzezinski, Jack, primary, Luo, Ping, primary, Hansford, Jordan R., primary, Cairney, Elizabeth, primary, Portwine, Carol, primary, Elser, Christine, primary, Finlay, Jonathan L., primary, Nichols, Kim E., primary, Alon, Noa, primary, Brunga, Ledia, primary, Anson, Jo, primary, Kohlmann, Wendy, primary, de Andrade, Kelvin C., primary, Khincha, Payal P., primary, Savage, Sharon A., primary, Schiffman, Joshua D., primary, Weksberg, Rosanna, primary, Pugh, Trevor J., primary, Villani, Anita, primary, Shlien, Adam, primary, Goldenberg, Anna, primary, and Malkin, David, primary

Published
2023
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7. FIGURE 2 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Author

Subasri, Vallijah, primary, Light, Nicholas, primary, Kanwar, Nisha, primary, Brzezinski, Jack, primary, Luo, Ping, primary, Hansford, Jordan R., primary, Cairney, Elizabeth, primary, Portwine, Carol, primary, Elser, Christine, primary, Finlay, Jonathan L., primary, Nichols, Kim E., primary, Alon, Noa, primary, Brunga, Ledia, primary, Anson, Jo, primary, Kohlmann, Wendy, primary, de Andrade, Kelvin C., primary, Khincha, Payal P., primary, Savage, Sharon A., primary, Schiffman, Joshua D., primary, Weksberg, Rosanna, primary, Pugh, Trevor J., primary, Villani, Anita, primary, Shlien, Adam, primary, Goldenberg, Anna, primary, and Malkin, David, primary

Published
2023
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8. FIGURE 3 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Author

Subasri, Vallijah, primary, Light, Nicholas, primary, Kanwar, Nisha, primary, Brzezinski, Jack, primary, Luo, Ping, primary, Hansford, Jordan R., primary, Cairney, Elizabeth, primary, Portwine, Carol, primary, Elser, Christine, primary, Finlay, Jonathan L., primary, Nichols, Kim E., primary, Alon, Noa, primary, Brunga, Ledia, primary, Anson, Jo, primary, Kohlmann, Wendy, primary, de Andrade, Kelvin C., primary, Khincha, Payal P., primary, Savage, Sharon A., primary, Schiffman, Joshua D., primary, Weksberg, Rosanna, primary, Pugh, Trevor J., primary, Villani, Anita, primary, Shlien, Adam, primary, Goldenberg, Anna, primary, and Malkin, David, primary

Published
2023
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9. TABLE 1 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Author

Subasri, Vallijah, primary, Light, Nicholas, primary, Kanwar, Nisha, primary, Brzezinski, Jack, primary, Luo, Ping, primary, Hansford, Jordan R., primary, Cairney, Elizabeth, primary, Portwine, Carol, primary, Elser, Christine, primary, Finlay, Jonathan L., primary, Nichols, Kim E., primary, Alon, Noa, primary, Brunga, Ledia, primary, Anson, Jo, primary, Kohlmann, Wendy, primary, de Andrade, Kelvin C., primary, Khincha, Payal P., primary, Savage, Sharon A., primary, Schiffman, Joshua D., primary, Weksberg, Rosanna, primary, Pugh, Trevor J., primary, Villani, Anita, primary, Shlien, Adam, primary, Goldenberg, Anna, primary, and Malkin, David, primary

Published
2023
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10. TABLE 2 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Author

Subasri, Vallijah, primary, Light, Nicholas, primary, Kanwar, Nisha, primary, Brzezinski, Jack, primary, Luo, Ping, primary, Hansford, Jordan R., primary, Cairney, Elizabeth, primary, Portwine, Carol, primary, Elser, Christine, primary, Finlay, Jonathan L., primary, Nichols, Kim E., primary, Alon, Noa, primary, Brunga, Ledia, primary, Anson, Jo, primary, Kohlmann, Wendy, primary, de Andrade, Kelvin C., primary, Khincha, Payal P., primary, Savage, Sharon A., primary, Schiffman, Joshua D., primary, Weksberg, Rosanna, primary, Pugh, Trevor J., primary, Villani, Anita, primary, Shlien, Adam, primary, Goldenberg, Anna, primary, and Malkin, David, primary

Published
2023
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11. FIGURE 1 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Author

Subasri, Vallijah, primary, Light, Nicholas, primary, Kanwar, Nisha, primary, Brzezinski, Jack, primary, Luo, Ping, primary, Hansford, Jordan R., primary, Cairney, Elizabeth, primary, Portwine, Carol, primary, Elser, Christine, primary, Finlay, Jonathan L., primary, Nichols, Kim E., primary, Alon, Noa, primary, Brunga, Ledia, primary, Anson, Jo, primary, Kohlmann, Wendy, primary, de Andrade, Kelvin C., primary, Khincha, Payal P., primary, Savage, Sharon A., primary, Schiffman, Joshua D., primary, Weksberg, Rosanna, primary, Pugh, Trevor J., primary, Villani, Anita, primary, Shlien, Adam, primary, Goldenberg, Anna, primary, and Malkin, David, primary

Published
2023
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12. FIGURE 5 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Author

Subasri, Vallijah, primary, Light, Nicholas, primary, Kanwar, Nisha, primary, Brzezinski, Jack, primary, Luo, Ping, primary, Hansford, Jordan R., primary, Cairney, Elizabeth, primary, Portwine, Carol, primary, Elser, Christine, primary, Finlay, Jonathan L., primary, Nichols, Kim E., primary, Alon, Noa, primary, Brunga, Ledia, primary, Anson, Jo, primary, Kohlmann, Wendy, primary, de Andrade, Kelvin C., primary, Khincha, Payal P., primary, Savage, Sharon A., primary, Schiffman, Joshua D., primary, Weksberg, Rosanna, primary, Pugh, Trevor J., primary, Villani, Anita, primary, Shlien, Adam, primary, Goldenberg, Anna, primary, and Malkin, David, primary

Published
2023
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13. FIGURE 4 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Author

Subasri, Vallijah, primary, Light, Nicholas, primary, Kanwar, Nisha, primary, Brzezinski, Jack, primary, Luo, Ping, primary, Hansford, Jordan R., primary, Cairney, Elizabeth, primary, Portwine, Carol, primary, Elser, Christine, primary, Finlay, Jonathan L., primary, Nichols, Kim E., primary, Alon, Noa, primary, Brunga, Ledia, primary, Anson, Jo, primary, Kohlmann, Wendy, primary, de Andrade, Kelvin C., primary, Khincha, Payal P., primary, Savage, Sharon A., primary, Schiffman, Joshua D., primary, Weksberg, Rosanna, primary, Pugh, Trevor J., primary, Villani, Anita, primary, Shlien, Adam, primary, Goldenberg, Anna, primary, and Malkin, David, primary

Published
2023
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14. Supplementary Figures S1-S12 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Author

Subasri, Vallijah, primary, Light, Nicholas, primary, Kanwar, Nisha, primary, Brzezinski, Jack, primary, Luo, Ping, primary, Hansford, Jordan R., primary, Cairney, Elizabeth, primary, Portwine, Carol, primary, Elser, Christine, primary, Finlay, Jonathan L., primary, Nichols, Kim E., primary, Alon, Noa, primary, Brunga, Ledia, primary, Anson, Jo, primary, Kohlmann, Wendy, primary, de Andrade, Kelvin C., primary, Khincha, Payal P., primary, Savage, Sharon A., primary, Schiffman, Joshua D., primary, Weksberg, Rosanna, primary, Pugh, Trevor J., primary, Villani, Anita, primary, Shlien, Adam, primary, Goldenberg, Anna, primary, and Malkin, David, primary

Published
2023
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15. Data from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Author

Subasri, Vallijah, primary, Light, Nicholas, primary, Kanwar, Nisha, primary, Brzezinski, Jack, primary, Luo, Ping, primary, Hansford, Jordan R., primary, Cairney, Elizabeth, primary, Portwine, Carol, primary, Elser, Christine, primary, Finlay, Jonathan L., primary, Nichols, Kim E., primary, Alon, Noa, primary, Brunga, Ledia, primary, Anson, Jo, primary, Kohlmann, Wendy, primary, de Andrade, Kelvin C., primary, Khincha, Payal P., primary, Savage, Sharon A., primary, Schiffman, Joshua D., primary, Weksberg, Rosanna, primary, Pugh, Trevor J., primary, Villani, Anita, primary, Shlien, Adam, primary, Goldenberg, Anna, primary, and Malkin, David, primary

Published
2023
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16. Multiple germline events contribute to cancer development in patients with Li-Fraumeni syndrome

Author

Subasri, Vallijah, primary, Light, Nicholas, additional, Kanwar, Nisha, additional, Brzezinski, Jack, additional, Luo, Ping, additional, Hansford, Jordan R, additional, Cairney, Elizabeth, additional, Portwine, Carol, additional, Elser, Christine, additional, Finlay, Jonathan L., additional, Nichols, Kim E., additional, Alon, Noa, additional, Brunga, Ledia, additional, Anson, Jo, additional, Kohlmann, Wendy, additional, de Andrade, Kelvin C., additional, Khincha, Payal P., additional, Savage, Sharon A., additional, Schiffman, Joshua D, additional, Weksberg, Rosanna, additional, Pugh, Trevor J., additional, Villani, Anita, additional, Shlien, Adam, additional, Goldenberg, Anna, additional, and Malkin, David, additional

Published
2023
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19. Abstract 1428: DNA methylation predicts early onset of primary tumor in patients with Li-Fraumeni syndrome

Author

Subasri, Vallijah, primary, Brew, Benjamin, additional, Erdman, Lauren, additional, Guha, Tanya, additional, Hansford, Jordan R., additional, Cairney, Elizabeth, additional, Portwine, Carol, additional, Elser, Christine, additional, Finlay, Jonathan L., additional, Nichols, Kim E., additional, Kohlmann, Wendy, additional, Alon, Noa, additional, Novokmet, Ana, additional, Brunga, Ledia, additional, Villani, Anita, additional, de Andrade, Kelvin C., additional, Khincha, Payal P., additional, Savage, Sharon A., additional, Schiffman, Joshua D., additional, Malkin, David, additional, and Goldenberg, Anna, additional

Published
2022
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20. Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants

Author

Fortuno, Cristina, Lee, Kristy, Olivier, Magali, Pesaran, Tina, Mai, Phuong L, de Andrade, Kelvin C, Attardi, Laura D, Crowley, Stephanie, Evans, D Gareth, Feng, Bing-Jian, Foreman, Ann KM, Frone, Megan N, Huether, Robert, James, Paul A, McGoldrick, Kelly, Mester, Jessica, Seifert, Bryce A, Slavin, Thomas P, Witkowski, Leora, Zhang, Liying, Plon, Sharon E, Spurdle, Amanda B, Savage, Sharon A, and ClinGen TP53 Variant Curation Expert Panel

Subjects
Genetics & Heredity, Prevention, Human Genome, Clinical Sciences, Genetic Variation, United States, Li-Fraumeni Syndrome, ClinGen TP53 Variant Curation Expert Panel, Germ Cells, pathogenic variant, Good Health and Well Being, Genetics, Humans, cancer, 2.1 Biological and endogenous factors, Genetic Testing, TP53, variant curation, Tumor Suppressor Protein p53, Aetiology
Abstract

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, including early-onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for 20 ACMG/AMP criteria, while nine were deemed not applicable. The original strength level for the 10 criteria was also adjusted due to current evidence. Use of TP53-specific guidelines and sharing of clinical data amongexperts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53-specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification.

Published
2021

21. Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia

Author

Savage, Sharon A., Viard, Mathias, O’hUigin, Colm, Zhou, Weiyin, Yeager, Meredith, Li, Shengchao Alfred, Wang, Tao, Ramsuran, Veron, Vince, Nicolas, Vogt, Aurelie, Hicks, Belynda, Burdett, Laurie, Chung, Charles, Dean, Michael, de Andrade, Kelvin C., Freedman, Neal D., Berndt, Sonja I., Rothman, Nathaniel, Lan, Qing, Cerhan, James R., Slager, Susan L., Zhang, Yawei, Teras, Lauren R., Haagenson, Michael, Chanock, Stephen J., Spellman, Stephen R., Wang, Youjin, Willis, Amanda, Askar, Medhat, Lee, Stephanie J., Carrington, Mary, and Gadalla, Shahinaz M.

Published
2020
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22. Pathogenic germline IKZF1 variant alters hematopoietic gene expression profiles

Author

Brodie, Seth A., primary, Khincha, Payal P., additional, Giri, Neelam, additional, Bouk, Aaron J., additional, Steinberg, Mia, additional, Dai, Jieqiong, additional, Jessop, Lea, additional, Donovan, Frank X., additional, Chandrasekharappa, Settara C., additional, de Andrade, Kelvin C., additional, Maric, Irina, additional, Ellis, Steven R., additional, Mirabello, Lisa, additional, Alter, Blanche P., additional, and Savage, Sharon A., additional

Published
2021
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23. Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study

Author

Kim, Jung, primary, Gianferante, Matthew, additional, Karyadi, Danielle M, additional, Hartley, Stephen W, additional, Frone, Megan N, additional, Luo, Wen, additional, Robison, Leslie L, additional, Armstrong, Gregory T, additional, Bhatia, Smita, additional, Dean, Michael, additional, Yeager, Meredith, additional, Zhu, Bin, additional, Song, Lei, additional, Sampson, Joshua N, additional, Yasui, Yutaka, additional, Leisenring, Wendy M, additional, Brodie, Seth A, additional, de Andrade, Kelvin C, additional, Fortes, Fernanda P, additional, Goldstein, Alisa M, additional, Khincha, Payal P, additional, Machiela, Mitchell J, additional, McMaster, Mary L, additional, Nickerson, Michael L, additional, Oba, Leatrisse, additional, Pemov, Alexander, additional, Pinheiro, Maisa, additional, Rotunno, Melissa, additional, Santiago, Karina, additional, Wegman-Ostrosky, Talia, additional, Diver, W Ryan, additional, Teras, Lauren, additional, Freedman, Neal D, additional, Hicks, Belynda D, additional, Wang, Mingyi, additional, Jones, Kristine, additional, Hutchinson, Amy A, additional, Dagnall, Casey, additional, Savage, Sharon A, additional, Tucker, Margaret A, additional, Chanock, Stephen J, additional, Morton, Lindsay M, additional, Stewart, Douglas R, additional, and Mirabello, Lisa, additional

Published
2021
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24. XAF1 as a modifier of p53 function and cancer susceptibility

Author

Pinto, Emilia M., primary, Figueiredo, Bonald C., additional, Chen, Wenan, additional, Galvao, Henrique C.R., additional, Formiga, Maria Nirvana, additional, Fragoso, Maria Candida B.V., additional, Ashton-Prolla, Patricia, additional, Ribeiro, Enilze M.S.F., additional, Felix, Gabriela, additional, Costa, Tatiana E.B., additional, Savage, Sharon A., additional, Yeager, Meredith, additional, Palmero, Edenir I., additional, Volc, Sahlua, additional, Salvador, Hector, additional, Fuster-Soler, Jose Luis, additional, Lavarino, Cinzia, additional, Chantada, Guillermo, additional, Vaur, Dominique, additional, Odone-Filho, Vicente, additional, Brugières, Laurence, additional, Else, Tobias, additional, Stoffel, Elena M., additional, Maxwell, Kara N., additional, Achatz, Maria Isabel, additional, Kowalski, Luis, additional, de Andrade, Kelvin C., additional, Pappo, Alberto, additional, Letouze, Eric, additional, Latronico, Ana Claudia, additional, Mendonca, Berenice B., additional, Almeida, Madson Q., additional, Brondani, Vania B., additional, Bittar, Camila M., additional, Soares, Emerson W.S., additional, Mathias, Carolina, additional, Ramos, Cintia R.N., additional, Machado, Moara, additional, Zhou, Weiyin, additional, Jones, Kristine, additional, Vogt, Aurelie, additional, Klincha, Payal P., additional, Santiago, Karina M., additional, Komechen, Heloisa, additional, Paraizo, Mariana M., additional, Parise, Ivy Z.S., additional, Hamilton, Kayla V., additional, Wang, Jinling, additional, Rampersaud, Evadnie, additional, Clay, Michael R., additional, Murphy, Andrew J., additional, Lalli, Enzo, additional, Nichols, Kim E., additional, Ribeiro, Raul C., additional, Rodriguez-Galindo, Carlos, additional, Korbonits, Marta, additional, Zhang, Jinghui, additional, Thomas, Mark G., additional, Connelly, Jon P., additional, Pruett-Miller, Shondra, additional, Diekmann, Yoan, additional, Neale, Geoffrey, additional, Wu, Gang, additional, and Zambetti, Gerard P., additional

Published
2020
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25. Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants

Author

Fortuno, Cristina, primary, Lee, Kristy, additional, Olivier, Magali, additional, Pesaran, Tina, additional, Mai, Phuong L., additional, de Andrade, Kelvin C., additional, Attardi, Laura D., additional, Crowley, Stephanie, additional, Evans, D. Gareth, additional, Feng, Bing-Jian, additional, Major Foreman, Ann Katherine, additional, Frone, Megan N., additional, Huether, Robert, additional, James, Paul A., additional, McGoldrick, Kelly, additional, Mester, Jessica, additional, Seifert, Bryce A., additional, Slavin, Thomas P., additional, Witkowski, Leora, additional, Zhang, Liying, additional, Plon, Sharon E., additional, Spurdle, Amanda B., additional, and Savage, Sharon A., additional

Published
2020
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26. Prevalence of pathogenic/likely pathogenic variants in the 24 cancer genes of the ACMG Secondary Findings v2.0 list in a large cancer cohort and ethnicity-matched controls

Author

Kim, Jung, primary, Luo, Wen, additional, Wang, Mingyi, additional, Wegman-Ostrosky, Talia, additional, Frone, Megan N., additional, Johnston, Jennifer J., additional, Nickerson, Michael L., additional, Rotunno, Melissa, additional, Li, Shengchao A., additional, Achatz, Maria I., additional, Brodie, Seth A., additional, Dean, Michael, additional, de Andrade, Kelvin C., additional, Fortes, Fernanda P., additional, Gianferante, Matthew, additional, Khincha, Payal, additional, McMaster, Mary L., additional, McReynolds, Lisa J., additional, Pemov, Alexander, additional, Pinheiro, Maisa, additional, Santiago, Karina M., additional, Alter, Blanche P., additional, Caporaso, Neil E., additional, Gadalla, Shahinaz M., additional, Goldin, Lynn R., additional, Greene, Mark H., additional, Loud, Jennifer, additional, Yang, Xiaohong R., additional, Freedman, Neal D., additional, Gapstur, Susan M., additional, Gaudet, Mia M., additional, Calista, Donato, additional, Ghiorzo, Paola, additional, Fargnoli, Maria Concetta, additional, Nagore, Eduardo, additional, Peris, Ketty, additional, Puig, Susana, additional, Landi, Maria Teresa, additional, Hicks, Belynda, additional, Zhu, Bin, additional, Liu, Jia, additional, Sampson, Joshua N., additional, Chanock, Stephen J., additional, Mirabello, Lisa J., additional, Morton, Lindsay M., additional, Biesecker, Leslie G., additional, Tucker, Margaret A., additional, Savage, Sharon A., additional, Goldstein, Alisa M., additional, and Stewart, Douglas R., additional

Published
2018
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27. Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis

Author

de Andrade, Kelvin C., primary, Frone, Megan N., additional, Wegman-Ostrosky, Talia, additional, Khincha, Payal P., additional, Kim, Jung, additional, Amadou, Amina, additional, Santiago, Karina M., additional, Fortes, Fernanda P., additional, Lemonnier, Nathanaël, additional, Mirabello, Lisa, additional, Stewart, Douglas R., additional, Hainaut, Pierre, additional, Kowalski, Luiz P., additional, Savage, Sharon A., additional, and Achatz, Maria I., additional

Published
2018
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28. Pathogenic germline IKZF1 variant alters hematopoietic gene expression profiles.

Author

Brodie SA, Khincha PP, Giri N, Bouk AJ, Steinberg M, Dai J, Jessop L, Donovan FX, Chandrasekharappa SC, de Andrade KC, Maric I, Ellis SR, Mirabello L, Alter BP, and Savage SA

Subjects
Gene Expression Regulation, Humans, Infant, Male, Mutation, Missense, Pedigree, Protein Isoforms genetics, Protein Stability, Transcriptome, Anemia, Diamond-Blackfan genetics, Diseases in Twins genetics, Germ-Line Mutation, Hematopoiesis genetics, Ikaros Transcription Factor genetics
Abstract

IKZF1 encodes Ikaros, a zinc finger-containing transcription factor crucial to the development of the hematopoietic system. Germline pathogenic variants in IKZF1 have been reported in patients with acute lymphocytic leukemia and immunodeficiency syndromes. Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by erythroid hypoplasia, associated with a spectrum of congenital anomalies and an elevated risk of certain cancers. DBA is usually caused by heterozygous pathogenic variants in genes that function in ribosomal biogenesis; however, in many cases the genetic etiology is unknown. We identified a germline IKZF1 variant, rs757907717 C > T, in identical twins with DBA-like features and autoimmune gastrointestinal disease. rs757907717 C > T results in a p.R381C amino acid change in the IKZF1 Ik-x isoform (p.R423C on isoform Ik-1), which we show is associated with altered global gene expression and perturbation of transcriptional networks involved in hematopoietic system development. These data suggest that this missense substitution caused a DBA-like syndrome in this family because of alterations in hematopoiesis, including dysregulation of networks essential for normal erythropoiesis and the immune system., (© 2021 Brodie et al.; Published by Cold Spring Harbor Laboratory Press.)

Published
2021
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29. Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants.

Author

Fortuno C, Lee K, Olivier M, Pesaran T, Mai PL, de Andrade KC, Attardi LD, Crowley S, Evans DG, Feng BJ, Foreman AKM, Frone MN, Huether R, James PA, McGoldrick K, Mester J, Seifert BA, Slavin TP, Witkowski L, Zhang L, Plon SE, Spurdle AB, and Savage SA

Subjects
Genetic Testing, Germ Cells, Humans, United States, Genetic Variation, Li-Fraumeni Syndrome diagnosis, Li-Fraumeni Syndrome genetics, Tumor Suppressor Protein p53 genetics
Abstract

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, including early-onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for 20 ACMG/AMP criteria, while nine were deemed not applicable. The original strength level for the 10 criteria was also adjusted due to current evidence. Use of TP53-specific guidelines and sharing of clinical data among experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53-specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification., (Published 2020. This article is a U.S. Goverment work and is in the public domain in the USA.)

Published
2021
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31. Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis.

Author

de Andrade KC, Frone MN, Wegman-Ostrosky T, Khincha PP, Kim J, Amadou A, Santiago KM, Fortes FP, Lemonnier N, Mirabello L, Stewart DR, Hainaut P, Kowalski LP, Savage SA, and Achatz MI

Subjects
Humans, Middle Aged, Databases, Genetic, Genetics, Population, Germ-Line Mutation genetics, Molecular Sequence Annotation, Tumor Suppressor Protein p53 genetics
Abstract

Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regarding the prevalence of pathogenic germline TP53 variants. We previously reported higher-than-expected population prevalence estimates in sequencing databases composed of individuals unselected for cancer history. This study aimed to expand and further evaluate the prevalence of pathogenic and likely pathogenic germline TP53 variants in the gnomAD dataset (version r2.0.2, n = 138,632). Variants were selected and classified based on our previously published algorithm and compared with alternative estimates based on three different classification databases: ClinVar, HGMD, and the UMD_TP53 database. Conservative prevalence estimates of pathogenic and likely pathogenic TP53 variants were within the range of one carrier in 3,555-5,476 individuals. Less stringent classification increased the approximate prevalence to one carrier in every 400-865 individuals, mainly due to the inclusion of the controvertible p.N235S, p.V31I, and p.R290H variants. This study shows a higher-than-expected population prevalence of pathogenic and likely pathogenic germline TP53 variants even with the most conservative estimates. However, these estimates may not necessarily reflect the prevalence of the classical LFS phenotype, which is based upon family history of cancer. Comprehensive approaches are needed to better understand the interplay of germline TP53 variant classification, prevalence estimates, cancer penetrance, and LFS-associated phenotype., (© 2018 Wiley Periodicals, Inc.)

Published
2019
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