Submissions for variant NM_000051.4(ATM):c.4465C>T (p.Arg1489Cys)

gnomAD frequency: 0.00001  dbSNP: rs754181173

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459393	SCV000546828	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1489 of the ATM protein (p.Arg1489Cys). This variant is present in population databases (rs754181173, gnomAD 0.002%). 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: 407548). 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.
GeneDx	RCV000766502	SCV000564641	uncertain significance	not provided	2022-05-08	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as germline pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28652578, 28481359, 29484624, 33471991)
Genetic Services Laboratory, University of Chicago	RCV000483688	SCV000593503	uncertain significance	not specified	2016-10-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569181	SCV000665199	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-11	criteria provided, single submitter	clinical testing	The p.R1489C variant (also known as c.4465C>T), located in coding exon 29 of the ATM gene, results from a C to T substitution at nucleotide position 4465. The arginine at codon 1489 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000569181	SCV000687550	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1489 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 3/60463 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 2/251294 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.
Illumina Laboratory Services, Illumina	RCV000459393	SCV001264583	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-12	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000483688	SCV002041567	uncertain significance	not specified	2021-11-14	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4465C>T (p.Arg1489Cys) 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 allele was found at a frequency of 1.1e-05 in 269134 control chromosomes, however the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4465C>T has not been reported in the literature in individuals affected with Ataxia-Telangiectasia, however they have been reported in individuals affected with Breast Cancer (Dorling_2021). This report does not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003470419	SCV004207062	uncertain significance	Familial cancer of breast	2024-03-17	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766502	SCV001744471	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766502	SCV001954322	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000459393	SCV002084737	uncertain significance	Ataxia-telangiectasia syndrome	2020-08-12	no assertion criteria provided	clinical testing