Heterozygous Pathogenic Nonsense ATM Variant Resulting in Unusually High Gastric Cancer Susceptibility

Abstract We describe the unusual presentation of familial early-onset gastric cancer due to a heterozygous pathogenic variant in the ATM gene. The proband had gastric cancer (age 45), and reported a sister deceased for 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, TP53) identified the truncating c.5944C>T, p.(Gln1982*) variant in ATM (NM_000051.3; NP_000042.3) in the proband. The variant segregated in the living affected sister and in the unaffected daughter of the deceased sister. Heterozygous ATM variants appear to significantly increase the risk for pancreatic, breast, gastric and prostatic cancer and, to a reduced extent, ovarian and colon cancer and melanoma, with moderate penetrance and variable expressivity. Familial gastric cancer is an unusual presentation for ATM. The occurrence of gastric cancer in this family suggests that individual variants may result in different, specific risks. Genotype-phenotype correlations are challenging, given the low penetrance and variable expressivity for ATM variants. Careful family history assessment is pivotal for prevention planning, strengthened by the availability of molecular diagnoses.