Submissions for variant NM_000051.4(ATM):c.5189G>T (p.Arg1730Leu)

dbSNP: rs373789346

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463817	SCV000546731	uncertain significance	Ataxia-telangiectasia syndrome	2023-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1730 of the ATM protein (p.Arg1730Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with late-onset ataxia and breast cancer (PMID: 22071889). ClinVar contains an entry for this variant (Variation ID: 407496). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000580727	SCV000682255	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 1730 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with late-onset ataxia-telangiectasia and breast cancer (PMID: 21665257, 22071889) and in an individual affected with breast cancer (PMID: 29665859). 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.
Ambry Genetics	RCV000580727	SCV002641482	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	The p.R1730L variant (also known as c.5189G>T), located in coding exon 34 of the ATM gene, results from a G to T substitution at nucleotide position 5189. The arginine at codon 1730 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been previously reported in an individual with a clinical diagnosis of ataxia-telangiectasia (AT) along with another ATM alteration; however, information about the phase (cis vs trans) of these two alterations was not provided (Micol R et al. J. Allergy Clin. Immunol., 2011 Aug;128:382-9.e1). Cell lines from another individual with AT who was heterozygous for this alteration along with a second alteration in ATM, exhibited decreased response to ionizing radiation, decreased ATM protein expression, and abnormal cellular localization (Jacquemin V et al. Eur. J. Hum. Genet., 2012 Mar;20:305-12). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701498	SCV005205372	uncertain significance	not specified	2024-06-03	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5189G>T (p.Arg1730Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251120 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5189G>T has been reported in the literature in at least one compound heterozygous individual affected with Ataxia-Telangiectasia who also developed breast cancer (Jacquemin_2012). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22071889, 21665257, 29665859). ClinVar contains an entry for this variant (Variation ID: 407496). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000463817	SCV002080928	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-08	no assertion criteria provided	clinical testing