Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53
Summary: Disease-causing variants with penetrance that is lower than the average expected for a given gene complicate classification, even when using gene-specific guidelines. For TP53, a gene associated with some of the highest cancer risks, even reduced penetrance disease-predisposition variants r...
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| Language: | English |
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Elsevier
2025-10-01
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| Series: | HGG Advances |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247725000879 |
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| author | Cristina Fortuno Marcy E. Richardson Tina Pesaran Kelly McGoldrick Paul A. James Amanda B. Spurdle |
| author_facet | Cristina Fortuno Marcy E. Richardson Tina Pesaran Kelly McGoldrick Paul A. James Amanda B. Spurdle |
| author_sort | Cristina Fortuno |
| collection | DOAJ |
| description | Summary: Disease-causing variants with penetrance that is lower than the average expected for a given gene complicate classification, even when using gene-specific guidelines. For TP53, a gene associated with some of the highest cancer risks, even reduced penetrance disease-predisposition variants remain clinically actionable. We conducted a review of ClinVar submissions to identify TP53 variants flagged as having reduced penetrance by genetic testing laboratories and analyzed functional, bioinformatic, immunogenicity, frequency, and clinical features of these variants compared with standard pathogenic and benign variants. Our findings show that reported reduced penetrance TP53 variants are more likely to exhibit intermediate functional activity in multiple assays and are predicted as deleterious with bioinformatic tools, though with lower scores than pathogenic variants. These variants also have a higher population frequency than pathogenic variants, and heterozygotes tend to manifest disease later in life, suggesting a need for refined clinical criteria to better capture attenuated Li-Fraumeni syndrome phenotypes. Finally, by applying a random forest prediction model to all TP53 uncertain or conflicting variants in ClinVar, we identified 106 additional variants with potential reduced penetrance. |
| format | Article |
| id | doaj-art-410bbac4c62b4b42a58ece80d768f4ac |
| institution | DOAJ |
| issn | 2666-2477 |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj-art-410bbac4c62b4b42a58ece80d768f4ac2025-08-20T03:15:42ZengElsevierHGG Advances2666-24772025-10-016410048410.1016/j.xhgg.2025.100484Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53Cristina Fortuno0Marcy E. Richardson1Tina Pesaran2Kelly McGoldrick3Paul A. James4Amanda B. Spurdle5Population Health Program, QIMR Berghofer, Herston, QLD 4006, AustraliaAmbry Genetics, Aliso Viejo, CA, USAAmbry Genetics, Aliso Viejo, CA, USAAmbry Genetics, Aliso Viejo, CA, USAParkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, AustraliaPopulation Health Program, QIMR Berghofer, Herston, QLD 4006, Australia; Faculty of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia; Corresponding authorSummary: Disease-causing variants with penetrance that is lower than the average expected for a given gene complicate classification, even when using gene-specific guidelines. For TP53, a gene associated with some of the highest cancer risks, even reduced penetrance disease-predisposition variants remain clinically actionable. We conducted a review of ClinVar submissions to identify TP53 variants flagged as having reduced penetrance by genetic testing laboratories and analyzed functional, bioinformatic, immunogenicity, frequency, and clinical features of these variants compared with standard pathogenic and benign variants. Our findings show that reported reduced penetrance TP53 variants are more likely to exhibit intermediate functional activity in multiple assays and are predicted as deleterious with bioinformatic tools, though with lower scores than pathogenic variants. These variants also have a higher population frequency than pathogenic variants, and heterozygotes tend to manifest disease later in life, suggesting a need for refined clinical criteria to better capture attenuated Li-Fraumeni syndrome phenotypes. Finally, by applying a random forest prediction model to all TP53 uncertain or conflicting variants in ClinVar, we identified 106 additional variants with potential reduced penetrance.http://www.sciencedirect.com/science/article/pii/S2666247725000879reduced penetrancepenetranceLi-Fraumeni syndromevariant classificationACMGClinGen |
| spellingShingle | Cristina Fortuno Marcy E. Richardson Tina Pesaran Kelly McGoldrick Paul A. James Amanda B. Spurdle Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53 HGG Advances reduced penetrance penetrance Li-Fraumeni syndrome variant classification ACMG ClinGen |
| title | Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53 |
| title_full | Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53 |
| title_fullStr | Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53 |
| title_full_unstemmed | Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53 |
| title_short | Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53 |
| title_sort | characteristics predicting reduced penetrance variants in the high risk cancer predisposition gene tp53 |
| topic | reduced penetrance penetrance Li-Fraumeni syndrome variant classification ACMG ClinGen |
| url | http://www.sciencedirect.com/science/article/pii/S2666247725000879 |
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