Assessing germline TP53 mutations in cancer patients: insights into Li-Fraumeni syndrome and genetic testing guidelines

Danishevich, Anastasiia; Fedorova, Daria; Bodunova, Natalia; Makarova, Maria; Byakhova, Maria; Semenova, Anna; Galkin, Vsevolod; Litvinova, Maria; Nikolaev, Sergey; Efimova, Irina; Osinin, Pavel; Lisitsa, Tatyana; Khakhina, Anastasiya; Shipulin, German; Nasedkina, Tatiana; Shumilova, Syuykum; Gusev, Oleg; Bilyalov, Airat; Shagimardanova, Elena; Shigapova, Leyla; Nemtsova, Marina; Sagaydak, Olesya; Woroncow, Mary; Gadzhieva, Saida; Khatkov, Igor

doi:10.1186/s13053-025-00307-w

Hereditary Cancer in Clinical Practice

Table 4 Clinical and anamnestic characteristics of patients with identified TP53 variants

From: Assessing germline TP53 mutations in cancer patients: insights into Li-Fraumeni syndrome and genetic testing guidelines

	Sex	MN sites	Age (diagnosis)	Criteria Chompret	Family history	SNV (hg38) NM_000546.5	SNV location in the *TP53* gene	ACMG classification	LOF class, func	SpliceAI results (delta scores)
P01	F	MPMN: 1) right breast	36	No	Mother—breast cancer, died at 28	chr17:g.7675995G > C c.374C > G p.Thr125Arg	Ex 4	P	LOF + , NF	AL 0.07 DL 0.07 AG 0.00 DG 0.15
P01	F	2) left breast	38	No	Mother—breast cancer, died at 28	chr17:g.7675995G > C c.374C > G p.Thr125Arg	Ex 4	P	LOF + , NF	AL 0.07 DL 0.07 AG 0.00 DG 0.15
P02	F	left breast	36	Yes	CNS Sarcoma	chr17:g.7675237C > G c.376-1G > C	Int 4	P	N/A, N/A	AL 1.00 DL 0.04 AG 0.98 DG 0.04
P03	F	right breast	35	Yes	CNS Stomach Sarcoma	chr17:g.7675139C > T c.473G > A p.Arg158His	Ex 5	P	LOF + , NF	AL 0.00 DL 0.00 AG 0.00 DG 0.00
P04	F	left breast	28	Yes	negative	chr17:g.7675088C > T c.524G > A p.Arg175His	Ex 5	P	LOF + , NF	AL 0.00 DL 0.00 AG 0.00 DG 0.01
P05	F	right breast	38	No	breast cancer Lungs	chr17:g.7675070C > T, c.542G > A, p.Arg181His	Ex 5	P	LOF-, PF	AL 0.01 DL 0.00 AG 0.00 DG 0.02
P06	F	MPMN: 1) right breast	47	No	breast cancer Lungs	chr17:g.7675070C > T, c.542G > A, p.Arg181His	Ex 5	P	LOF-, PF	AL 0.01 DL 0.00 AG 0.00 DG 0.02
P06	F	2) left breast	47	No	breast cancer Lungs	chr17:g.7675070C > T, c.542G > A, p.Arg181His	Ex 5	P	LOF-, PF	AL 0.01 DL 0.00 AG 0.00 DG 0.02
P07	F	left breast	33	No	negative	chr17:g.7675053C > T, c.559G > A, p.Gly187Ser	Ex 5	LP	LOF-, N/A	AL 0.12 DL 0.05 AG 0.00 DG 0.56
P08	F	MPMN: 1) Hodgkin's lymphoma IIIBst (variant of nodular sclerosis)	20	Yes	Maternal aunt—breast cancer at 50 y.o	chr17:g.7674220C > T, c.743G > A, p.Arg248Gln	Ex 7	P	LOF + , NF	AL 0.00 DL 0.00 AG 0.00 DG 0.00
P08	F	2) left breast	29	Yes	Maternal aunt—breast cancer at 50 y.o	chr17:g.7674220C > T, c.743G > A, p.Arg248Gln	Ex 7	P	LOF + , NF	AL 0.00 DL 0.00 AG 0.00 DG 0.00
P09	F	right breast	49	No	Mother—breast cancer at 55 y.o	chr17:g.7674220C > T, c.743G > A, p.Arg248Gln	Ex 7	P	LOF + , NF	AL 0.00 DL 0.00 AG 0.00 DG 0.00
P10	F	left breast	29	Yes	negative	chr17:g.7674200 TGATGGTGAG > T c.754_762del, p.Leu252_Ile254del	Ex 7	P	N/A, N/A	AL 0.01 DL 0.00 AG 0.03 DG 0.00
P11	F	MPMN: 1) right breast	55	No	Grandmother—CC at 75 y.o	chr17:g.7673821G > A c. 799C > T p.Arg267Trp	Ex 8	P	LOF-, N/A	AL 0.02 DL 0.00 AG 0.04 DG 0.00
P11	F	2) left breast	55	No	Grandmother—CC at 75 y.o	chr17:g.7673821G > A c. 799C > T p.Arg267Trp	Ex 8	P	LOF-, N/A	AL 0.02 DL 0.00 AG 0.04 DG 0.00
P12	F	right breast	38	No	negative	chr17:7673820C > T c.800G > A p.Arg267Gln	Ex 8	LP	LOF-, PF	AL 0.04 DL 0.00 AG 0.08 DG 0.00
P13	F	left breast	66	No	Maternal grandmother—RC	chr17:7673802C > T, c.818G > A, p.Arg273His	Ex 8	P	LOF + , NF	AL 0.02 DL 0.00 AG 0.01 DG 0.00

The Cancer Pedigrees, see Fig. 3. The SpliceAI results column contains delta scores acquired from SpliceAI in silico predictor [16]. Delta scores range from 0 to 1 and can be interpreted as the probability that the variant affects splicing at any position within a window around it (in our case—± 500 base pairs window was used). All the delta scores exceeding the recommended cutoff (0.5) were highlighted in red
Abbreviations MN Malignant neoplasms, BC breast cancer, CC colon cancer, RC rectal cancer, MPMN multiple primary malignant neoplasms, ACMG recommendations American College of Medical Genetics and Genomics on the interpretation of genetic variants, P pathogenic, LP likely pathogenic, LOF ± – “loss of function” presence [17], NF non-functional variant, PF partially functional [18], N/A no data available, AL acceptor loss score, DL donor loss score, AG acceptor gain score, DG donor gain score

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