ClinVar Genomic variation as it relates to human health

AXIN2: BP4

The AXIN2 variant designated as NM_004655.3:c.1168A>G (p.Ser390Gly) is classified as likely benign. This variant has been reported in several population databases. It is present in approximately 1 in 350 individuals with European ancestry (http://gnomad.broadinstitute.org/). This population frequency is much higher than other pathogenic variants in AXIN2 and not consistent with the reported oligodontia-cancer syndrome frequency. This variant has been reported as likely benign by other laboratories (ClinVar Variation ID: 127934). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter AXIN2 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

This variant is associated with the following publications: (PMID: 27300758, 30374176)

Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 59 year old with a history of over 50 colon polyps.

The AXIN2 p.Ser390Gly variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs139871607) and ClinVar (classified as likely benign by Illumina, Invitae and the University of Washington Department of Laboratory Medicine and as uncertain significance by GeneDx, Mayo Clinic Genetic Testing Laboratories and the CSER_CC_NCGL; University of Washington Medical Center). The variant was also identified in control databases in 210 of 282220 chromosomes at a frequency of 0.000744 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 183 of 128706 chromosomes (freq: 0.001422), Other in 7 of 7206 chromosomes (freq: 0.000971), European (Finnish) in 8 of 25094 chromosomes (freq: 0.000319), African in 5 of 24886 chromosomes (freq: 0.000201) and Latino in 7 of 35408 chromosomes (freq: 0.000198), but was not observed in the Ashkenazi Jewish, East Asian or South Asian populations. The p.Ser390 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant also occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).