Submissions for variant NM_004655.4(AXIN2):c.1685C>T (p.Pro562Leu)

gnomAD frequency: 0.00031  dbSNP: rs149764887

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115869	SCV000149778	uncertain significance	not provided	2021-02-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with primary melanoma but also in healthy controls (Pedace 2011); This variant is associated with the following publications: (PMID: 21294210, 26224873, 27739435, 28717660)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230720	SCV000288672	likely benign	Oligodontia-cancer predisposition syndrome	2025-02-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000230720	SCV000405690	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.
Ambry Genetics	RCV001012728	SCV001173217	likely benign	Hereditary cancer-predisposing syndrome	2018-10-29	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.
Baylor Genetics	RCV000230720	SCV001482768	uncertain significance	Oligodontia-cancer predisposition syndrome	2019-01-17	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000115869	SCV002009785	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001012728	SCV002537099	likely benign	Hereditary cancer-predisposing syndrome	2021-03-29	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265608	SCV002548341	benign	not specified	2022-05-02	criteria provided, single submitter	clinical testing	Variant summary: AXIN2 c.1685C>T (p.Pro562Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 249918 control chromosomes (gnomAD), predominantly at a frequency of 0.00064 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in AXIN2 causing Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1685C>T has been reported in the literature in individuals of Non-Finnish European ancestry affected tooth agenesis (Keskin_2021), Colorectal Cancer (Chan_2021), and Breast Cancer (Moradian_2021). These reports do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002265608	SCV002761004	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115869	SCV002774096	likely benign	not provided	2023-03-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000115869	SCV003917969	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	AXIN2: BP4
Clinical Genetics, Academic Medical Center	RCV000115869	SCV001920165	likely benign	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000115869	SCV001963511	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000115869	SCV001971090	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529933	SCV004738625	likely benign	AXIN2-related disorder	2023-07-03	no assertion criteria provided	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).