Submission Details

CTNNA1 gene encodes a member of the catenin family of proteins that is associated with both E-cadherin (encoded by CDH1 gene) and N-cadherin. The complexes play an important role in cell adhesion process by connecting cadherins located on the plasma membrane to the actin filaments inside the cell. CTNNA1 was first reported in relation to autosomal dominant hereditary diffuse gastric cancer (HDGC) syndrome in 2013 (Majewski et al, PMID: 23208944). Similar to pathogenic variants of CDH1 gene, which are associated with lobular breast cancer (LBC) in addition to HDGC, we found that some patients with pathogenic CTNNA1 variants were also diagnosed with LBC. Additionally, per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in inheritance pattern and molecular mechanism; therefore, this curation has lumped HDGC and LBC as a disease term, CTNNA1-related diffuse gastric and lobular breast cancer syndrome. Please note, CTNNA1 is associated with patterned macular dystrophy 2 (MONDO:0012162), which was split from this curation due to phenotypic variability, and variant type differences. Fourteen variants (nonsense, splice site and frameshift) that have been reported in 16 probands (15 with diffuse gastric cancer and one with lobular breast cancer) described in 7 publications (PMIDs:23208944, 26182300, 29330337, 30515673, 29025585, 32051609 and 36038258) are included in this curation. The mechanism of pathogenicity is reported as heterozygous loss of function (LOF). In a large cohort of 151,425 individuals with personal/family history of cancer (Clark et al, 2020 PMID: 32051609) LOF variants in this gene were also identified in unaffected individuals and individuals with other cancer types suggesting the spectrum of cancers may change over time. This gene-disease relationship is also supported by experimental evidence (protein interactions, cellular and animal models, expression studies) (PMIDs:2788574, 9023354, 11239416, 12080224, 29774524 and 22080244). Experimental evidence shows that CTNNA1 is a protein involved in the adherens junctions (AJ) that binds cadherin/β-catenin to actin cytoskeleton, promoting cell adhesion. In summary, there is definitive evidence to support the relationship between CTNNA1 and autosomal dominant hereditary diffuse gastric cancer and lobular breast cancer. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was curated on 02/23/2023 by the Hereditary Cancer GCEP (SOP Version 9).