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

Omran, Meis ; Liu, Yaxuan ; Sun Zhang, Alexander ; Poluha, Anna ; Stenmark-Askmalm, Marie LU ; Persson, Fredrik ; Hallbeck, Anna Lotta ; Rosén, Anna ; Helgadottir, Hafdis T. and Tham, Emma , et al. (2025) In European Journal of Human Genetics
Abstract

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... (More)

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 22 were 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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organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
European Journal of Human Genetics
article number
738
publisher
Nature Publishing Group
external identifiers
  • pmid:39757328
  • scopus:85214091294
ISSN
1018-4813
DOI
10.1038/s41431-024-01753-1
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2025.
id
aacf0ae1-4102-40c0-9ab0-5c04bc4d0656
date added to LUP
2025-03-24 15:09:17
date last changed
2025-06-30 21:13:36
@article{aacf0ae1-4102-40c0-9ab0-5c04bc4d0656,
  abstract     = {{<p>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 22 were missense. The most frequently observed variant was the missense c.542 G &gt; 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.</p>}},
  author       = {{Omran, Meis and Liu, Yaxuan and Sun Zhang, Alexander and Poluha, Anna and Stenmark-Askmalm, Marie and Persson, Fredrik and Hallbeck, Anna Lotta and Rosén, Anna and Helgadottir, Hafdis T. and Tham, Emma and Bajalica-Lagercrantz, Svetlana}},
  issn         = {{1018-4813}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{European Journal of Human Genetics}},
  title        = {{Characterisation of heritable TP53-related cancer syndrome in Sweden—a nationwide study of genotype-phenotype correlations in 90 families}},
  url          = {{http://dx.doi.org/10.1038/s41431-024-01753-1}},
  doi          = {{10.1038/s41431-024-01753-1}},
  year         = {{2025}},
}