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Characterisation of heritable TP53-related cancer syndrome in Sweden—a nationwide study of genotype-phenotype correlations in 90 families

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Title: Characterisation of heritable TP53-related cancer syndrome in Sweden—a nationwide study of genotype-phenotype correlations in 90 families
Authors: Omran, Meis, Liu, Yaxuan, Sun Zhang, Alexander, Poluha, Anna, Stenmark-Askmalm, Marie, Persson, Fredrik, Hallbeck, Anna Lotta, Rosén, Anna, Helgadottir, Hafdis T., Tham, Emma, Bajalica-Lagercrantz, Svetlana
Contributors: Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Clinical Genetics, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för klinisk genetik, Originator
Source: European Journal of Human Genetics. 33(4):513-522
Subject Terms: Medical and Health Sciences, Clinical Medicine, Cancer and Oncology, Medicin och hälsovetenskap, Klinisk medicin, Cancer och onkologi, Basic Medicine, Medical Genetics and Genomics (including Gene Therapy), Medicinska och farmaceutiska grundvetenskaper, Medicinsk genetik och genomik (Här ingår: Genterapi)
Description: We aimed to describe the clinical characteristics of families with heritable TP53-related cancer (hTP53rc) syndrome in Sweden with class 4 and 5 germline TP53 variants (gTP53), and to evaluate the genotype-phenotype correlation. These results were also used to evaluate our previously published phenotype prediction model based on TP53 missense variants and their impact on protein conformation. 90 families with hTP53rc were initially identified in Sweden. After variant reclassification using the TP53-specific ACMG criteria, 83 families remained (176 carriers) to harbour a pathogenic (class 5) or likely pathogenic (class 4) variant in TP53. Of these, 112 carriers (64%) had a previous history of cancer, and 35 (31%) had developed more than one primary tumour. 16% of the families met the stricter criteria for Classic Li-Fraumeni syndrome, 45% the updated Chompret criteria, 35% for hereditary breast cancer (HBC), and the remaining 5% were classified as “Others”. We identified 42 different gTP53 variants of which 22were missense. The most frequently observed variant was the missense c.542 G > A, p.R181H identified in 14/29 (48%) of HBC families. Fifteen of the 20 informative missense variants (75%) were phenotypically predicted correctly using our previously published in silico prediction model. The TP53 p.R181H was identified as a common Swedish variant predominantly associated with an HBC phenotype. Apart from this variant, there were no significant genotype-phenotype correlations. Therefore, due to phenotypic overlap it is still too early to stratify surveillance programme for different TP53-carriers.
Access URL: https://doi.org/10.1038/s41431-024-01753-1
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  Data: Characterisation of heritable TP53-related cancer syndrome in Sweden—a nationwide study of genotype-phenotype correlations in 90 families
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  Data: <searchLink fieldCode="AR" term="%22Omran%2C+Meis%22">Omran, Meis</searchLink><br /><searchLink fieldCode="AR" term="%22Liu%2C+Yaxuan%22">Liu, Yaxuan</searchLink><br /><searchLink fieldCode="AR" term="%22Sun+Zhang%2C+Alexander%22">Sun Zhang, Alexander</searchLink><br /><searchLink fieldCode="AR" term="%22Poluha%2C+Anna%22">Poluha, Anna</searchLink><br /><searchLink fieldCode="AR" term="%22Stenmark-Askmalm%2C+Marie%22">Stenmark-Askmalm, Marie</searchLink><br /><searchLink fieldCode="AR" term="%22Persson%2C+Fredrik%22">Persson, Fredrik</searchLink><br /><searchLink fieldCode="AR" term="%22Hallbeck%2C+Anna+Lotta%22">Hallbeck, Anna Lotta</searchLink><br /><searchLink fieldCode="AR" term="%22Rosén%2C+Anna%22">Rosén, Anna</searchLink><br /><searchLink fieldCode="AR" term="%22Helgadottir%2C+Hafdis+T%2E%22">Helgadottir, Hafdis T.</searchLink><br /><searchLink fieldCode="AR" term="%22Tham%2C+Emma%22">Tham, Emma</searchLink><br /><searchLink fieldCode="AR" term="%22Bajalica-Lagercrantz%2C+Svetlana%22">Bajalica-Lagercrantz, Svetlana</searchLink>
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  Data: Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Clinical Genetics, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för klinisk genetik, Originator
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  Data: <i>European Journal of Human Genetics</i>. 33(4):513-522
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  Data: <searchLink fieldCode="DE" term="%22Medical+and+Health+Sciences%22">Medical and Health Sciences</searchLink><br /><searchLink fieldCode="DE" term="%22Clinical+Medicine%22">Clinical Medicine</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+and+Oncology%22">Cancer and Oncology</searchLink><br /><searchLink fieldCode="DE" term="%22Medicin+och+hälsovetenskap%22">Medicin och hälsovetenskap</searchLink><br /><searchLink fieldCode="DE" term="%22Klinisk+medicin%22">Klinisk medicin</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+och+onkologi%22">Cancer och onkologi</searchLink><br /><searchLink fieldCode="DE" term="%22Basic+Medicine%22">Basic Medicine</searchLink><br /><searchLink fieldCode="DE" term="%22Medical+Genetics+and+Genomics+%28including+Gene+Therapy%29%22">Medical Genetics and Genomics (including Gene Therapy)</searchLink><br /><searchLink fieldCode="DE" term="%22Medicinska+och+farmaceutiska+grundvetenskaper%22">Medicinska och farmaceutiska grundvetenskaper</searchLink><br /><searchLink fieldCode="DE" term="%22Medicinsk+genetik+och+genomik+%28Här+ingår%3A+Genterapi%29%22">Medicinsk genetik och genomik (Här ingår: Genterapi)</searchLink>
– Name: Abstract
  Label: Description
  Group: Ab
  Data: We aimed to describe the clinical characteristics of families with heritable TP53-related cancer (hTP53rc) syndrome in Sweden with class 4 and 5 germline TP53 variants (gTP53), and to evaluate the genotype-phenotype correlation. These results were also used to evaluate our previously published phenotype prediction model based on TP53 missense variants and their impact on protein conformation. 90 families with hTP53rc were initially identified in Sweden. After variant reclassification using the TP53-specific ACMG criteria, 83 families remained (176 carriers) to harbour a pathogenic (class 5) or likely pathogenic (class 4) variant in TP53. Of these, 112 carriers (64%) had a previous history of cancer, and 35 (31%) had developed more than one primary tumour. 16% of the families met the stricter criteria for Classic Li-Fraumeni syndrome, 45% the updated Chompret criteria, 35% for hereditary breast cancer (HBC), and the remaining 5% were classified as “Others”. We identified 42 different gTP53 variants of which 22were missense. The most frequently observed variant was the missense c.542 G > A, p.R181H identified in 14/29 (48%) of HBC families. Fifteen of the 20 informative missense variants (75%) were phenotypically predicted correctly using our previously published in silico prediction model. The TP53 p.R181H was identified as a common Swedish variant predominantly associated with an HBC phenotype. Apart from this variant, there were no significant genotype-phenotype correlations. Therefore, due to phenotypic overlap it is still too early to stratify surveillance programme for different TP53-carriers.
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