Submissions for variant NM_000051.4(ATM):c.1468A>G (p.Ile490Val)

dbSNP: rs761850075

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227312	SCV000282872	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 490 of the ATM protein (p.Ile490Val). This variant is present in population databases (rs761850075, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 236673). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics	RCV001011720	SCV001172076	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	clinical testing	The p.I490V variant (also known as c.1468A>G), located in coding exon 9 of the ATM gene, results from an A to G substitution at nucleotide position 1468. The isoleucine at codon 490 is replaced by valine, an amino acid with highly similar properties. This alteration was seen in 0/732 breast cancer patients, 1/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other 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	RCV001011720	SCV001351462	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-20	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 490 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Baylor Genetics	RCV003469120	SCV004210052	uncertain significance	Familial cancer of breast	2023-08-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000227312	SCV001461005	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing