Submissions for variant NM_004655.4(AXIN2):c.1201-2A>G

gnomAD frequency: 0.00001  dbSNP: rs775783026

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000548467	SCV000639070	likely pathogenic	Oligodontia-cancer predisposition syndrome	2022-10-11	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 5 of the AXIN2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AXIN2 are known to be pathogenic (PMID: 15042511, 21416598). 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 variant has not been reported in the literature in individuals affected with AXIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 464525). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV001010281	SCV001170454	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	The c.1201-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 5 in the AXIN2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
GeneDx	RCV002259348	SCV002538819	uncertain significance	not provided	2022-06-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant with an unclear effect on protein function and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Observed in an individual with glioblastoma (Huang 2018); This variant is associated with the following publications: (PMID: 29625052)
MGZ Medical Genetics Center	RCV000548467	SCV002581338	likely pathogenic	Oligodontia-cancer predisposition syndrome	2022-03-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000548467	SCV004044568	likely pathogenic	Oligodontia-cancer predisposition syndrome	2023-05-17	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Baylor Genetics	RCV003476263	SCV004210760	likely pathogenic	Colorectal cancer	2023-10-22	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV001824820	SCV002075149	not provided	AXIN2-related attenuated familial adenomatous polyposis		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 01-10-2020 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.