PMC8440986_01
Family pedigree indicating the genotype and phenotype of each individual. + and - indicate the TP53 pathogenic variant c.645del (p.Ser215Argfs*32) and TP53 reference allele, respectively. Different colors indicate liver cancers, pancreatic cancer, osteosarcoma, breast cancer, ovarian cancer, thyroid cancer, brain tumor, gastric cancer, colorectal cancer, spinocellular carcinoma, and soft tissue sarcoma. d, age of death; Dx, age of diagnosis.
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F1
The proband (III.2) is a 64-year-old deceased male affected by liver cancer, having two healthy daughters and one 20-year-old deceased son affected by osteosarcoma (Figure 1). All the proband's relatives affected by typical LFS cancers (I.2, II.2, III.14, III.22, IV.10, IV.21, IV.22, Figure 1) were deceased and did not receive any genetic testing.
(A) Snapshot of Integrative Genomics Viewer, showing the TP53 germline variant c.645del (p.Ser215Argfs*32) in the proband (III.2). (B) Sanger sequencing showing the c.645del pathogenic heterozygous TP53 variant in the proband (III.2), his son (IV.4), his brother (III.10), his sister (III.13), and his first female cousin (III.21). WT TP53 allele is shown in proband's brother (III.6), proband's brother (III.8), proband's niece (IV.19), and proband's nephew (IV.20). The red arrow indicates the heterozygous deletion.
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F2
NGS analysis showed a heterozygous frameshift TP53 variant ([GRCh37/hg19] chr17: g.7578204delA; NM_000546.6: c.645del (p.Ser215Argfs*32) in the exon 6 of the TP53 (III.2, Figure 2A). Sanger sequencing confirmed the presence in the proband of the heterozygous frameshift c.645del variant in the exon 6 of the TP53 gene (Figure 2B). Importantly, the proband's son (IV.4, Figure 2B), deceased at the age of 20 due to osteosarcoma, was a heterozygous carrier of the c.645del Finally, the proband's niece (IV.19), who has a diagnosis of breast cancer at the age of 34, and the proband's nephew (IV.20), who was healthy, were found to have wild-type TP53 alleles (Figure 2B).