ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with non-syndromic tooth agenesis as well as individuals with a personal or family history including colorectal, sarcoma, and other cancers (Pedace 2011, Ballinger 2016, Raskin 2017, Haddaji Mastouri 2018); This variant is associated with the following publications: (PMID: 29114927, 28640387, 12101426, 21294210, 25236910, 15735151, 15538750, 15067328, 27498913, 29212164, 33193653)

Variant summary: AXIN2 c.1975C>T (p.Arg659Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 245028 control chromosomes. The observed variant frequency is approximately 2 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 benign. c.1975C>T has been reported in the literature in at least one individual affected with Colorectal Cancer. These reports do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

This alteration is classified as likely 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.