Clinical Domain Working Groups

Somatic variants in MAPK/ERK pathway genes are known to play important role in hematologic and solid tumors. This VCEP would work on creating MAPK/ERK pathway genes specific version of ClinGen/CGC/VICC SOP for the Classification of Pathogenicity of Somatic Variants in Cancer and AMP/ASCO/CAP clinical guidelines and provide the curation results based on developed guidelines in ClinVar and CIViC. Specifically, we are considering genes encoding core members and regulators of MAPK/ERK pathway (PTPN11, KRAS, NRAS, HRAS, BRAF, RAF1, ARAF, MAP2K1, MAPK1) as the initial set of genes in which to evaluate pathogenicity/oncogenicity and clinical significance in terms of therapeutic, diagnostic, prognostic implications of somatic variants. These genes are well known as oncogenes in multiple types of hematologic and solid tumors, and somatic pathogenic variants in these genes are well known to have important clinical implications. As key players of MAPK/ERK pathway these genes have significant overlap in underlying molecular biology and therefore represent a logical group of genes for curation. The following types of somatic variants will be covered: missense, nonsense/frameshift, splice sites, small insertions, deletions. The major therapies for curation will include inhibitors of BRAF, MAP2K1, KRAS, MAPK1, and PTPN11.