Heterozygous Pathogenic Nonsense Variant in the ATM Gene in a Family with Unusually High Gastric Cancer Susceptibility

Daniele Guadagnolo; Gioia Mastromoro; Enrica Marchionni; Aldo Germani; Fabio Libi; Soha Sadeghi; Camilla Savio; Simona Petrucci; Laura De Marchis; Maria Piane; Antonio Pizzuti

doi:10.3390/biomedicines11072062

Heterozygous Pathogenic Nonsense Variant in the ATM Gene in a Family with Unusually High Gastric Cancer Susceptibility

Biomedicines. 2023 Jul 22;11(7):2062. doi: 10.3390/biomedicines11072062.

Authors

Daniele Guadagnolo¹, Gioia Mastromoro¹, Enrica Marchionni¹, Aldo Germani^{2

3}, Fabio Libi³, Soha Sadeghi^{2

3}, Camilla Savio³, Simona Petrucci^{2

3}, Laura De Marchis^{4

5}, Maria Piane^{2

3}, Antonio Pizzuti¹

Affiliations

¹ Department of Experimental Medicine, School of Medicine and Dentistry, Sapienza University of Rome, 00185 Rome, Italy.
² Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, 00185 Rome, Italy.
³ Medical Genetics Unit, Department of Diagnostic Sciences, Sant'Andrea University Hospital, 00189 Rome, Italy.
⁴ Department of Radiological, Oncological and Anatomopathological Science, Sapienza University of Rome, 00185 Rome, Italy.
⁵ Oncology B Unit, Department of Hematology, Dermatology and Oncology, Policlinico Umberto I Univeristy Hospital, 00161 Rome, Italy.

Abstract

Germline pathogenic variants (PVs) in the Ataxia Telangiectasia mutated (ATM) gene (MIM* 607585) increase the risk for breast, pancreatic, gastric, and prostatic cancer and, to a reduced extent, ovarian and colon cancer and melanoma, with moderate penetrance and variable expressivity. We describe a family presenting early-onset gastric cancer and harboring a heterozygous pathogenic ATM variant. The proband had gastric cancer (age 45) and reported a sister deceased due to diffuse gastric cancer (age 30) and another sister who developed diffuse gastric cancer (age 52) and ovarian serous cancer. Next generation sequencing for cancer susceptibility genes (APC, ATM, BRD1, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL1, SMAD4, STK11, and TP53) was performed. Molecular analysis identified the truncating c.5944C>T, p.(Gln1982*) variant in the ATM (NM_000051.3; NP_000042.3) in the proband. The variant had segregated in the living affected sister and in the unaffected daughter of the deceased affected sister. Familial early-onset gastric cancer is an unusual presentation for ATM-related malignancies. Individual variants may result in different specific risks. Genotype-phenotype correlations are challenging given the low penetrance and variable expressivity. Careful family history assessments are pivotal for prevention planning and are strengthened by the availability of molecular diagnoses.

Keywords: ATM; cancer susceptibility; gastric cancer.

Publication types

Case Reports

Grants and funding

The study received no external funding. The Article Processing Charge was covered by the Italian Ministry of University and Research.