Submissions for variant NM_000051.4(ATM):c.8494C>T (p.Arg2832Cys)

gnomAD frequency: 0.00001  dbSNP: rs587779872

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV001197256	SCV004565390	likely pathogenic	Familial cancer of breast	2024-01-25	reviewed by expert panel	curation	The c.8494C>T variant in ATM is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 2832 (p.Arg2832Cys). This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 26896183, 22017321, 26846839). The highest minor allele frequency in gnomAD v2.1.1 of 0.01% (2/16244 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor, Revel (Score: 0.83), predicts a damaging effect on ATM function. Additionally, experimental studies showed that this variant has impact on ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type (PMID: 18634022). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3_Strong, PP3, PS3_supporting)
GeneDx	RCV000212084	SCV000149174	pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced ATM protein levels and reduced or absent ATM kinase activity (Becker-Catania et al., 2000; Sun et al., 2002; Butch et al., 2004; Chun and Gatti, 2004; Barone et al., 2009; Mitui et al., 2009; Reiman et al., 2011; Fievet et al., 2019; Schon et al., 2019); Observed in the heterozygous state in individuals with ATM-related cancers (Schroeder et al., 2015; Hansen et al., 2017; Renault et al., 2018; Girard et al., 2019); 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: 15503472, 25793145, 9443866, 16448697, 29665859, 32980694, 29922827, 28888541, 12673797, 12072877, 20301790, 23091097, 15486025, 19431188, 10817650, 25040471, 12497634, 18634022, 15279807, 27135926, 26681312, 26312527, 26022348, 28008555, 28195393, 12552559, 22529920, 25827173, 30093976, 30549301, 31050087, 21792198, 22017321, 23532176, 29625052, 30875412, 35264596, 34926252, 35737913, 33328602, 35486574, 33471991, 32155193, 36988593, 35454905, 35365198, 36521553, 26896183, 26846839, 21665257, 10873394, 30303537)
Ambry Genetics	RCV000115265	SCV000186811	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	clinical testing	The p.R2832C pathogenic mutation (also known as c.8494C>T), located in coding exon 57 of the ATM gene, results from a C to T substitution at nucleotide position 8494. The arginine at codon 2832 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected both as the only mutation and in conjunction with a second mutation in many ataxia-telangiectasia (A-T) patients (Telatar M et al. Am. J. Hum. Genet. 1998 Jan;62:86-97; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Mitui M et al. Hum. Mutat. 2009 Jan;30:12-21). Functional analyses of p.R2832C have shown abolished kinase activity, reduced protein levels, and increased radiosensitivity compared to wild type ATM. In addition, four of five mild A-T patients carrying this alteration developed cancer, including breast cancers, melanoma, and hematologic malignancies. Three of four p.R2832C carrier mothers from these families developed breast cancer (Mitui M et al. Hum. Mutat. 2009 Jan;30:12-21). It was also seen in a patient with a personal and family history of colorectal cancer (Hansen MF et al. Clin. Genet. 2017 Oct;92:405-414). Of note, this alteration is also designated as R2831C in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000169354	SCV000220724	likely pathogenic	Ataxia-telangiectasia syndrome	2014-09-23	criteria provided, single submitter	literature only
Invitae	RCV000169354	SCV000260807	pathogenic	Ataxia-telangiectasia syndrome	2024-01-21	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 2832 of the ATM protein (p.Arg2832Cys). This variant is present in population databases (rs587779872, gnomAD 0.01%). This missense change has been observed in individuals with ataxia-telangiectasia and/or breast cancer (PMID: 9443866, 10817650, 10873394, 12552559, 18634022, 26681312). ClinVar contains an entry for this variant (Variation ID: 127459). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 10873394, 19431188). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000115265	SCV000682491	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2832 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). Functional studies have shown that this variant results in significantly reduced ATM protein expression and kinase activity, and intermediate radiosensitivity (PMID: 10873394, 18634022, 19431188, 22017321). This variant has also been observed homozygous or in compound heterozygous state with another pathogenic variant in individuals affected with ataxia-telangiectasia (PMID: 9443866, 10817650, 10873394, 12552559, 12673797, 18634022, 19147735, 19431188, 21792198, 22017321). This variant has also been reported in individuals affected with breast cancer (PMID: 18634022, 20301790, 26022348, 26681312, 28008555, 29665859, 30093976). This variant has been identified in 8/251268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000169354	SCV000809109	pathogenic	Ataxia-telangiectasia syndrome	2018-07-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000169354	SCV000838615	pathogenic	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197256	SCV001367893	likely pathogenic	Familial cancer of breast	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PP4,PP3.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000115265	SCV001448937	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-26	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001197256	SCV001499612	likely pathogenic	Familial cancer of breast	2020-04-02	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814061	SCV001755356	pathogenic	Abnormal central motor function	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000169354	SCV002020837	pathogenic	Ataxia-telangiectasia syndrome	2019-06-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115265	SCV002527352	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-23	criteria provided, single submitter	curation
Lifecell International Pvt. Ltd	RCV000169354	SCV003923315	pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing	A Homozygote Missense variant c.8494C>T in Exon 58 of the ATM gene that results in the amino acid substitution p.Arg2832Cys was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic. (Variation ID: 127459). The variant has been previously reported for Ataxia-Telangiectasia by Telatar M, et al., 1988. Experimental study revealed the missense variant affects the protein function (Mitui M, et al., 2009). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
CeGaT Center for Human Genetics Tuebingen	RCV000212084	SCV004042529	likely pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	ATM: PM1, PM2, PM5, PS3:Moderate, BP1
Baylor Genetics	RCV001197256	SCV004209520	pathogenic	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001197256	SCV004933083	likely pathogenic	Familial cancer of breast	2024-02-02	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 18634022, 21792198]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10873394, 21665257].
GeneReviews	RCV000169354	SCV000328272	not provided	Ataxia-telangiectasia syndrome		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212084	SCV001963400	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000212084	SCV001968972	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169354	SCV002082548	pathogenic	Ataxia-telangiectasia syndrome	2018-01-05	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162536	SCV002758111	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences	RCV000169354	SCV003936079	pathogenic	Ataxia-telangiectasia syndrome		no assertion criteria provided	research