Abstract 1572: Inherited truncating RAD52 variant discovered using integrated germline- somatic analysis predicts clinical outcome in patients with lung cancers

Most of the heritability of lung cancer, estimated at 18% in population studies, remains unexplained. We employed a framework for variant interpretation utilizing integrated germline and somatic data.The lung cancer patients(pts) enrolled between 01/2014 and 05/2016 underwent sequencing analysis for 468 genes using MSK IMPACT with pathogenicity assessment performed using ACMG guidelines. Loss of heterozygosity (LOH) in tumor was inferred using the FACETS algorithm. A poorly characterized truncating variant was classified as “potential pathogenic variant” if we observed LOH of the relevant allele in the tumor and the gene was previously reported co-segregating in family studies or significant in genome wide association studies (GWAS). Frequencies of pathogenic germline variants were compared to population frequencies in the genome aggregation database (gnomAD).As per IRB protocol, germline results were anonymized for all cases. 2686 pts consented to tumor-normal sequencing of whom, 80% had lung adenocarcinoma, 10% squamous cell carcinoma and 5% small cell lung cancer diagnosis. We discovered a new truncating RAD52 p.Ser346Ter variant in 89 (3.3%) lung cancer patients; 47(53%) patients had LOH in tumor (23 pts with wild type allele loss and 24 patients with mutant allele loss). Previous lung cancer GWAS had reported common variants at the RAD52 locus as lung cancer susceptibility loci. The identified RAD52 truncating mutation may represent the functional variant within the risk haplotype. Clinico-pathological association with the RAD52 variant suggested that the mutation was more common in patients who had