Submissions for variant NM_004655.4(AXIN2):c.1387C>T (p.Arg463Cys)

dbSNP: rs730881395

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474692	SCV000548593	uncertain significance	Oligodontia-cancer predisposition syndrome	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 463 of the AXIN2 protein (p.Arg463Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with attenuated familial adenomatous polyposis (AFAP). The variant segregates with disease in this family (PMID: 23838596). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 408788). 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.
GeneDx	RCV001753887	SCV001985487	uncertain significance	not provided	2024-12-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed to segregate with disease in a family affected with attenuated familial adenomatous polyposis (AFAP) (PMID: 23838596); This variant is associated with the following publications: (PMID: 25236910, 30671715, 29223984, 34817745, 15735151, 37626374, 32807118, 23838596, 36502525)
Sema4, Sema4	RCV002257716	SCV002537056	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-30	criteria provided, single submitter	curation
Ambry Genetics	RCV002257716	SCV002699045	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-12	criteria provided, single submitter	clinical testing	The p.R463C variant (also known as c.1387C>T), located in coding exon 5 of the AXIN2 gene, results from a C to T substitution at nucleotide position 1387. The arginine at codon 463 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a family with attenuated familial adenomatous polyposis, without oligodontia or ectodermal dysplasia (Rivera B et al, Eur J Hum Genet. 2014 Mar;22:423-6). 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.
Baylor Genetics	RCV004568025	SCV005053225	uncertain significance	Colorectal cancer	2023-11-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005027517	SCV005650972	uncertain significance	Oligodontia-cancer predisposition syndrome; Colorectal cancer	2024-04-26	criteria provided, single submitter	clinical testing