Submissions for variant NM_000051.4(ATM):c.375G>A (p.Met125Ile)

dbSNP: rs1591474725

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001021068	SCV001182637	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-23	criteria provided, single submitter	clinical testing	The p.M125I variant (also known as c.375G>A), located in coding exon 4 of the ATM gene, results from a G to A substitution at nucleotide position 375. The methionine at codon 125 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001021068	SCV001340733	uncertain significance	Hereditary cancer-predisposing syndrome	2019-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 125 of the ATM protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Splice site prediction tools suggest that this variant may create a new splice acceptor site; however, this prediction has not been investigated in published functional studies. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Natera, Inc.	RCV001827201	SCV002090833	uncertain significance	Ataxia-telangiectasia syndrome	2021-02-10	no assertion criteria provided	clinical testing