Germline EGFR c.2527G > A (p.V843I) variant and familial lung cancer.

Background: Somatic epidermal growth factor receptor (EGFR) pathogenic variants have been identified and are routinely tested in the molecular diagnosis of non-small cell lung cancer (NSCLC) as they represent a target for EGFR tyrosine kinase inhibitor (TKI) therapy. However, germline variants in EGFR are much less frequently reported.

Case Presentation: Herein, we report the case of a 46-year-old woman diagnosed with lung adenocarcinoma who was found to harbor a rare germline missense variant in exon 21 of EGFR: NM_005228.5(EGFR):c.2527G>A (p.V843I). In the tumor, this variant (Cosmic ID COSV51767379) was accompanied by a secondary, known pathogenic EGFR variant in cis, also occurring in exon 21, c.2573T>G (p.L858R) (Cosmic ID 6224). Her mother was previously diagnosed with poorly differentiated lung carcinoma and her tumor was also found to harbour the p.V843I variant but no other pathogenic variants. Notably, the proband's sister, diagnosed with a lung carcinoma with sarcomatous features at age 44, did not carry this variant or any other somatic or germline EGFR variants.

Conclusion: This is the second report of familial lung adenocarcinoma associated with the germline p.V843I variant, which remains classified as a variant of uncertain significance. The lack of segregation of this variant in the proband's affected sister illustrates the complexity with evaluating lung cancer predisposition factors. Currently, there is a paucity of data regarding the therapeutic outcomes of patients with tumors expressing this rare germline variant, therefore we propose an algorithm for the identification of at-risk individuals and families as the first step for their personalized management.