Submissions for variant NM_004655.4(AXIN2):c.2218C>T (p.Pro740Ser)

gnomAD frequency: 0.00012  dbSNP: rs370503213

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484911	SCV000572410	uncertain significance	not provided	2025-02-26	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528547	SCV000639154	uncertain significance	Oligodontia-cancer predisposition syndrome	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 740 of the AXIN2 protein (p.Pro740Ser). This variant is present in population databases (rs370503213, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 422840). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV001014781	SCV001175536	benign	Hereditary cancer-predisposing syndrome	2024-10-28	criteria provided, single submitter	clinical testing	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000528547	SCV004171481	uncertain significance	Oligodontia-cancer predisposition syndrome	2023-10-18	criteria provided, single submitter	clinical testing	The AXIN2 c.2218C>T (p.Pro740Ser) change has a maximum subpopulation frequency of 0.032% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with oligodontia-cancer predisposition syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484911	SCV004219308	uncertain significance	not provided	2023-07-21	criteria provided, single submitter	clinical testing	To the best of our knowledge, this variant has not been reported in individuals with AXIN2-related conditions in the published literature. The frequency of this variant in the general population, 0.00032 (8/24956 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV005018813	SCV005650954	uncertain significance	Oligodontia-cancer predisposition syndrome; Colorectal cancer	2024-06-17	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000528547	SCV001749365	not provided	Oligodontia-cancer predisposition syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 06-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.