Submissions for variant NM_000051.4(ATM):c.4397_4398delinsCG (p.Arg1466Pro)

dbSNP: rs886038217

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000242236	SCV000301669	uncertain significance	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000494153	SCV000581436	pathogenic	Hereditary cancer-predisposing syndrome	2024-04-08	criteria provided, single submitter	clinical testing	The c.4397_4398delGAinsCG pathogenic mutation (also known as p.R1466P), located in coding exon 28 of the ATM gene, results from an in-frame deletion of GA and insertion of CG at nucleotide positions 4397 to 4398. This results in the substitution of the arginine residue for a proline residue at codon 1466, an amino acid with dissimilar properties. This variant has been detected in trans with a pathogenic mutation in ATM in an individual with a clinical diagnosis of ataxia-telangiectasia (A-T) (Ambry internal data). In addition, an alteration resulting in the same protein change, c.4397G>C, has been identified in conjunction with a pathogenic ATM mutation in a cohort of individuals from the UK diagnosed with A-T (Jackson TJ et al. Dev Med Child Neurol. 2016 07;58:690-7). This alteration is located in the HEAT domain of the ATM protein and based on internal structural assessment, it is more disruptive than nearby known pathogenic variants (Drozdetskiy A et al. Nucleic Acids Res. 2015 Jul;43:W389-94; Perry J et al. Cell. 2003 Jan;112:151-5; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis and is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628135	SCV000749028	uncertain significance	Ataxia-telangiectasia syndrome	2023-02-11	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 26896183). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1466 of the ATM protein (p.Arg1466Pro). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. ClinVar contains an entry for this variant (Variation ID: 254753). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Color Diagnostics, LLC DBA Color Health	RCV000494153	SCV001354414	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 1466 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in the compound heterozygous state in an individual affected with autosomal recessive ataxia-telangiectasia (ClinVar SCV000581436.5), indicating that this variant contributes to disease. This variant has not been identified 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.
GeneDx	RCV001764228	SCV001990282	uncertain significance	not provided	2019-07-11	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge