ClinVar Genomic variation as it relates to human health

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32051609)

This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 244 of the CTNNA1 protein (p.Ile244Leu). This variant is present in population databases (rs371337206, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CTNNA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 662371). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CTNNA1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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.

The CTNNA1 c.730A>T variant is predicted to result in the amino acid substitution p.Ile244Leu. This variant was reported in an individuals with gastric or breast cancer (Table S1, Clark et al. 2020. PubMed ID: 32051609). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-138160360-A-T). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/662371/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

The CTNNA1 p.Ile121Leu variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs371337206), ClinVar (classified as uncertain significance by Invitae), and LOVD 3.0 (variant effect not shared). The variant was identified in control databases in 11 of 268282 chromosomes at a frequency of 0.000041 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: African in 7 of 23612 chromosomes (freq: 0.000297), Other in 1 of 6706 chromosomes (freq: 0.000149), South Asian in 2 of 30524 chromosomes (freq: 0.000066) and East Asian in 1 of 19252 chromosomes (freq: 0.000052), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish), or European (non-Finnish) populations. The p.Ile121 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant 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. This variant is classified as a variant of uncertain significance.