Submissions for variant NM_000051.4(ATM):c.7375C>T (p.Arg2459Cys)

gnomAD frequency: 0.00003  dbSNP: rs730881383

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165342	SCV000216066	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-14	criteria provided, single submitter	clinical testing	The p.R2459C variant (also known as c.7375C>T), located in coding exon 49 of the ATM gene, results from a C to T substitution at nucleotide position 7375. The arginine at codon 2459 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197298	SCV000254143	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-26	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 2459 of the ATM protein (p.Arg2459Cys). This variant is present in population databases (rs730881383, gnomAD 0.01%). This missense change has been observed in individual(s) with a high risk of breast, ovarian, or prostate cancer (PMID: 29522266, 29752822, 32658311, 33436325). ClinVar contains an entry for this variant (Variation ID: 185845). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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	RCV000512906	SCV000293600	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28652578, 30099369, 23585524, 19018867, 27479817, 25742471, 24983367, 29522266, 28667006, 26010451, 29752822, 33436325, 34803902, 32658311, 23532176, 35365198, 33471991, 34284872)
CeGaT Center for Human Genetics Tuebingen	RCV000512906	SCV000608618	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165342	SCV000682410	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2459 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 performed for this variant. This variant has been observed in individuals affected with breast cancer (PMID: 29522266, 32658311, 33471991) and in an individual affected with chronic lymphocytic leukemia who also has a pathogenic ATM covariant (PMID: 19018867). This variant has also been observed in two healthy controls from a chronic lymphocytic leukemia case-control study (PMID: 28652578). This variant has been identified in 10/282668 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.
Fulgent Genetics, Fulgent Genetics	RCV000764943	SCV000896115	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2024-03-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193059	SCV001361639	uncertain significance	not specified	2020-11-19	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7375C>T (p.Arg2459Cys) results in a non-conservative amino acid change located in the PIK-related kinase (IPR014009) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251258 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7375C>T has been reported in the literature in individuals affected with Breast Cancer and Chronic Lymphocytic Leukemia (e.g. Cejkova_2008, Navrkalova_2013, Li_2018, Hauke_2018, Ackay_2020), and healthy controls (e.g. Tiao_2017). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000165342	SCV002537648	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-18	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV002288746	SCV002579617	uncertain significance	Familial cancer of breast	2021-12-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002288746	SCV004207767	uncertain significance	Familial cancer of breast	2024-03-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000512906	SCV004222133	uncertain significance	not provided	2024-11-19	criteria provided, single submitter	clinical testing	The ATM c.7375C>T (p.Arg2459Cys) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 33471991 (2021), 32658311 (2021), 29522266 (2018), 29752822 (2018)), prostate cancer (PMID: 33436325 (2021)), and in the somatic state in various cancers (PMIDs: 19018867 (2009), 23585524 (2013), 24983367 (2014)). It has also been described in reportedly healthy individuals (PMID: 35365198 (2022), 28652578 (2017)). The frequency of this variant in the general population, 0.000039 (5/129022 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Revvity Omics, Revvity	RCV000197298	SCV004234539	uncertain significance	Ataxia-telangiectasia syndrome	2023-03-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491896	SCV004239460	uncertain significance	Breast and/or ovarian cancer	2023-04-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288746	SCV005083928	likely benign	Familial cancer of breast	2024-06-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Natera, Inc.	RCV000197298	SCV001458468	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000512906	SCV002034883	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000512906	SCV002037218	uncertain significance	not provided		no assertion criteria provided	clinical testing