Submission Details

Activating missense and inframe deletion variants in the tyrosine kinase domain of EGFR are commonly reported in pre-treatment tumoral tissue analyses of individuals with non-small cell lung cancer. The relationship of germline variants in EGFR to autosomal dominant familial non-small cell lung cancer, adenocarcinoma subtype, was first reported in 2005 (Bell DW et al., PMIDs: 16258541). Two variants that have been reported in germline of twelve probands in eleven literature (PMIDs: 24736066, 16258541, 20068085, 20068085, 21252721, 22588155, 24736080, 18355544, 21172876, 23380224, 25176975, 23358982) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (7 pts.) has been reached. The mechanism for disease is gain-of-function. This gene-disease association is particularly supported for p.T790M germline variant by the number of families, animal models and in vitro functional assays on cell culture models where it has been shown to confer oncogenic properties such as tumor development and increased colony formation (PMIDs: 17726540, 17671201). There is also limited experimental evidence for p.V843I showing increased colony formation (PMID:25057940). In summary, EGFR is definitively associated with autosomal dominant familial non-small cell lung cancer susceptibility [MIM:211980]. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in molecular mechanisms (gain of function versus loss of function), inheritance pattern, and phenotypic variability between Non-small cell lung cancer, susceptibility to [MIM:211980] and Inflammatory skin and bowel disease, neonatal, 2 [MIM:616069]. Additionally, no cancer has been reported in both biallelic and monoallelic loss-of-function variant carriers.