Submissions for variant NM_004655.4(AXIN2):c.1168A>G (p.Ser390Gly)

gnomAD frequency: 0.00075  dbSNP: rs139871607

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656767	SCV000149775	likely benign	not provided	2020-10-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27300758, 30374176)
Invitae	RCV000227795	SCV000288645	likely benign	Oligodontia-cancer predisposition syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000227795	SCV000405709	benign	Oligodontia-cancer predisposition syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000227795	SCV000788238	likely benign	Oligodontia-cancer predisposition syndrome	2018-04-01	criteria provided, single submitter	research	The AXIN2 variant designated as NM_004655.3:c.1168A>G (p.Ser390Gly) is classified as likely benign. This variant has been reported in several population databases. It is present in approximately 1 in 350 individuals with European ancestry (http://gnomad.broadinstitute.org/). This population frequency is much higher than other pathogenic variants in AXIN2 and not consistent with the reported oligodontia-cancer syndrome frequency. This variant has been reported as likely benign by other laboratories (ClinVar Variation ID: 127934). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter AXIN2 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Ambry Genetics	RCV001010110	SCV001170258	likely benign	Hereditary cancer-predisposing syndrome	2018-12-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656767	SCV001473952	likely benign	not provided	2020-07-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000115866	SCV002051069	likely benign	not specified	2021-12-12	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000115866	SCV002068218	likely benign	not specified	2021-11-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001010110	SCV002537576	likely benign	Hereditary cancer-predisposing syndrome	2021-02-03	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000115866	SCV002551284	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115866	SCV002774024	benign	not specified	2021-08-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656767	SCV002822420	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	AXIN2: BP4
PreventionGenetics, part of Exact Sciences	RCV003952555	SCV004772762	likely benign	AXIN2-related condition	2020-09-15	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
CSER _CC_NCGL, University of Washington	RCV000417356	SCV000503528	uncertain significance	Oligodontia; Colorectal cancer	2016-08-01	no assertion criteria provided	research	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 59 year old with a history of over 50 colon polyps.
Mayo Clinic Laboratories, Mayo Clinic	RCV000115866	SCV000691790	uncertain significance	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656767	SCV001553020	likely benign	not provided		no assertion criteria provided	clinical testing	The AXIN2 p.Ser390Gly variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs139871607) and ClinVar (classified as likely benign by Illumina, Invitae and the University of Washington Department of Laboratory Medicine and as uncertain significance by GeneDx, Mayo Clinic Genetic Testing Laboratories and the CSER_CC_NCGL; University of Washington Medical Center). The variant was also identified in control databases in 210 of 282220 chromosomes at a frequency of 0.000744 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 183 of 128706 chromosomes (freq: 0.001422), Other in 7 of 7206 chromosomes (freq: 0.000971), European (Finnish) in 8 of 25094 chromosomes (freq: 0.000319), African in 5 of 24886 chromosomes (freq: 0.000201) and Latino in 7 of 35408 chromosomes (freq: 0.000198), but was not observed in the Ashkenazi Jewish, East Asian or South Asian populations. The p.Ser390 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant also occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.