ClinVar Genomic variation as it relates to human health

Variant summary: AXIN2 c.2013_2024del12 (p.Thr672_Arg675del) results in an in-frame deletion that is predicted to remove 4 amino acids from the encoded protein. The variant allele was found at a frequency of 0.0055 in 244704 control chromosomes, predominantly at a frequency of 0.075 within the African or African-American subpopulation in the gnomAD database, including 44 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 528-fold of the estimated maximal expected allele frequency for a pathogenic variant in AXIN2 causing Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. A co-occurrence with a pathogenic variant has been reported (PMS2 c.2186_2187delTC, p.Leu729GlnfsX6; Internal testing), providing further supporting evidence for a benign role. Three ClinVar submitters (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

This variant is associated with the following publications: (PMID: 26514524)

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.