Submissions for variant NM_004655.4(AXIN2):c.1906A>G (p.Ser636Gly)

gnomAD frequency: 0.00001  dbSNP: rs745616808

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475716	SCV000548622	uncertain significance	Oligodontia-cancer predisposition syndrome	2024-09-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 636 of the AXIN2 protein (p.Ser636Gly). This variant is present in population databases (rs745616808, gnomAD 0.003%). 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: 408815). 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. This missense change is associated with skipping of exon 7 (internal data). However, the skipping of exon 7 has been described as a tissue-specific functional isoform (also known as exon 6, PMID: 15735151). For this reason the clinical significance of this missense variant is currently uncertain. 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	RCV002411466	SCV002719925	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-05	criteria provided, single submitter	clinical testing	The p.S636G variant (also known as c.1906A>G), located in coding exon 6 of the AXIN2 gene, results from an A to G substitution at nucleotide position 1906. The serine at codon 636 is replaced by glycine, an amino acid with similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV002508214	SCV002817869	uncertain significance	not provided	2022-06-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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
Baylor Genetics	RCV003476073	SCV004213022	uncertain significance	Colorectal cancer	2023-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002508214	SCV005624956	uncertain significance	not provided	2024-06-18	criteria provided, single submitter	clinical testing	The AXIN2 c.1906A>G (p.Ser636Gly) variant has been identified in the published literature in a reportedly healthy individual (PMID: 29641532 (2018)). The frequency of this variant in the general population, 0.000008 (2/250780 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.