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<p>We aimed to describe the clinical characteristics of families with heritable <i>TP53</i>-related cancer (h<i>TP53</i>rc) syndrome in Sweden with class 4 and 5 germline <i>TP53</i> variants (g<i>TP53</i>), and to evaluate the genotype-phenotype correlation. These results were also used to evaluate our previously published phenotype prediction model based on <i>TP53</i> missense variants and their impact on protein conformation. 90 families with h<i>TP53</i>rc were initially identified in Sweden. After variant reclassification using the <i>TP53</i>-specific ACMG criteria, 83 families remained (176 carriers) to harbour a pathogenic (class 5) or likely pathogenic (class 4) variant in <i>TP53</i>. 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 g<i>TP53</i> 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 <i>TP53</i> 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 <i>TP53</i>-carriers.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月5日

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  • Meis Omran,
  • Yaxuan Liu,
  • Alexander Sun Zhang,
  • Anna Poluha,
  • Marie Stenmark-Askmalm,
  • Fredrik Persson,
  • Anna-Lotta Hallbeck,
  • Anna Rosén,
  • Hafdis T. Helgadottir,
  • Emma Tham,
  • Svetlana Bajalica-Lagercrantz

摘要

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.