Submissions for variant NM_004655.4(AXIN2):c.203G>A (p.Arg68Gln)

gnomAD frequency: 0.00020  dbSNP: rs138056036

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115872	SCV000149781	uncertain significance	not provided	2024-07-22	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Identified in individuals with personal and/or family history of colon cancer, attenuated adenomatous polyposis, or breast and/or ovarian cancer (PMID: 28944238, 31285513, 27153395); This variant is associated with the following publications: (PMID: 28944238, 31285513, 38136308, 27153395)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230597	SCV000288689	uncertain significance	Oligodontia-cancer predisposition syndrome	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 68 of the AXIN2 protein (p.Arg68Gln). This variant is present in population databases (rs138056036, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of AXIN2-related conditions (PMID: 28944238, 31285513). ClinVar contains an entry for this variant (Variation ID: 127940). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt AXIN2 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.
Ambry Genetics	RCV001014181	SCV001174863	likely benign	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	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.
Sema4, Sema4	RCV001014181	SCV002537143	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-05	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000230597	SCV002584759	uncertain significance	Oligodontia-cancer predisposition syndrome	2022-07-25	criteria provided, single submitter	clinical testing	The AXIN2 c.203G>A (p.Arg68Gln) missense change has a maximum subpopulation frequency of 0.026% 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. This variant has been reported in at least one individual with attenuated adenomatous polyposis (PMID: 31285513). 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	RCV000115872	SCV005624959	uncertain significance	not provided	2024-06-27	criteria provided, single submitter	clinical testing	The AXIN2 c.203G>A (p.Arg68Gln) variant has been reported in the published literature in an individual with attenuated adenomatous polyposis (PMID: 31285513 (2019)), an individual with colorectal cancer (PMID: 28944238 (2017)), an individual with breast and/or ovarian cancer (PMID: 27153395 (2016)), and an individual undergoing hereditary cancer testing (PMID: 38136308 (2023)). The frequency of this variant in the general population, 0.00026 (9/34930 chromosomes in Admixed 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.
Molecular Oncology Laboratory, Hospital Clínico San Carlos	RCV000230597	SCV000844928	uncertain significance	Oligodontia-cancer predisposition syndrome	2018-06-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004542822	SCV004757125	uncertain significance	AXIN2-related disorder	2023-12-20	no assertion criteria provided	clinical testing	The AXIN2 c.203G>A variant is predicted to result in the amino acid substitution p.Arg68Gln. This variant has been reported in an individual with attenuated adenomatous polyposis (Table 2, Lorca et al. 2019. PubMed ID: 31285513). This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/127940/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.