Submissions for variant NM_000051.4(ATM):c.4852C>T (p.Arg1618Ter)

gnomAD frequency: 0.00001  dbSNP: rs762083530

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166912	SCV000217730	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-25	criteria provided, single submitter	clinical testing	The p.R1618* pathogenic mutation (also known as c.4852C>T) located in coding exon 31 of the ATM gene, results from a C to T substitution at nucleotide position 4852. This changes the amino acid from an arginine to a stop codon within coding exon 31. This alteration has been described in multiple individuals with ataxia-telangiectasia (Hacia JG et al. Genome Res. 1998 Dec;8(12):1245-58; Babaei M et al. Hum. Genet. 2005 Jul;117:101-6; Micol R et al. J Allergy Clin Immunol, 2011 Aug;128:382-9.e1). This alteration has also been reported in individuals with breast, colorectal, pancreatic and prostate cancers (Paglia LL et al. Breast Cancer Res Treat, 2010 Jan;119:443-52; Hampel H et al. JAMA Oncol, 2018 06;4:806-813; Kondo T et al. Oncotarget, 2018 Apr;9:19817-19825; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000483137	SCV000568325	pathogenic	not provided	2022-06-30	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with ATM-related cancers (Paglia et al., 2010; Kondo et al., 2018); This variant is associated with the following publications: (PMID: 9872980, 25525159, 29731985, 31118792, 33436325, 32338768, 32853339, 33280026, 35428255, 33842585, 29922827, 15843990, 19404735)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000525721	SCV000622535	pathogenic	Ataxia-telangiectasia syndrome	2024-11-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1618*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs762083530, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia telangiectasia (PMID: 9872980, 15843990, 19404735). ClinVar contains an entry for this variant (Variation ID: 187207). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000166912	SCV000682226	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 32 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/251340 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Counsyl	RCV000525721	SCV000800324	pathogenic	Ataxia-telangiectasia syndrome	2018-05-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000525721	SCV001361263	pathogenic	Ataxia-telangiectasia syndrome	2019-08-29	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4852C>T (p.Arg1618X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251340 control chromosomes (gnomAD). c.4852C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Babaei_2005, Hacia_1998, Micol_2011) and in at least one individual affected with breast cancer (Paglia_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function using a cell line derived from a patient (who carried the variant of interest and another variant) demonstrated decreased phosphorylation of ATM target proteins, defective cell cycle checkpoint control following exposure to Camptothecin (CPT) and severely decreased ATM protein expression (Fievet_2019). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814077	SCV001755396	pathogenic	Abnormal central motor function	2021-07-10	criteria provided, single submitter	clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000166912	SCV001911464	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.4852C>T (p.Arg1618*) variant generates a stop codon that is predicted to result in a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It appears only once in the gnomAD v2.1.1 non-cancer dataset, specifically in the South Asian subpopulation (PM2; http://gnomad.broadinstitute.org). ). This variant has been reported in three ataxia-telangiectasia probands in homozygosis or heterozygosis (PS4_Moderate; PMID: 9872980, 15843990). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 + PS4_Moderate (PMID: 33280026).
Revvity Omics, Revvity	RCV000525721	SCV002020764	pathogenic	Ataxia-telangiectasia syndrome	2019-05-07	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV001808440	SCV002059660	pathogenic	Familial cancer of breast	2021-02-12	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000525721	SCV003841537	pathogenic	Ataxia-telangiectasia syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This homozygous variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000187207 / PMID: 9872980). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000525721	SCV004042688	pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001808440	SCV004215505	pathogenic	Familial cancer of breast	2024-01-12	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001808440	SCV004932976	pathogenic	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Neuberg Centre For Genomic Medicine, NCGM	RCV000525721	SCV005329413	pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing	The observed stop gained c.4852C>T(p.Arg1618Ter) variant in ATM gene has been reported in compound heterozygous or homozygous state in individuals affected with ataxia-telangiectasia (Hacia JG, et.al., 1998; Babaei M, et. al.,2005). Experimental evidence demonstrated decreased phosphorylation of ATM target proteins, defective cell cycle checkpoint control following exposure to Camptothecin (CPT) and severely decreased ATM protein expression (Fiévet A, et. al., 2019). This variant is present with an allele frequency of 0.0004% in gnomAD Exomes database. This variant has been submitted to ClinVar as pathogenic (multiple submissions). Computational evidence (MutationTaster - disease causing) predict a damaging effect on protein structure and function for this varian. The nucleotide change c.4852C>T in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Podralska MJ, et. al., 2014). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005042342	SCV005681294	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2024-03-28	criteria provided, single submitter	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162714	SCV002758279	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004739542	SCV005359135	pathogenic	ATM-related disorder	2024-05-23	no assertion criteria provided	clinical testing	The ATM c.4852C>T variant is predicted to result in premature protein termination (p.Arg1618*). This variant has been reported in the compound heterozygous and homozygous states in multiple individuals with autosomal recessive ataxia telangiectasia (Hacia et al. 1998. PubMed ID: 9872980; Babaei et al. 2005. PubMed ID: 15843990; Micol et al. 2011. PubMed ID: 21665257, Table E1). It has also been reported in an individual with breast cancer and a family history of breast and hematological malignancy (Paglia et al. 2010. PubMed ID: 19404735), and as a somatic change in a colorectal tumor specimen (Hampel et al. 2018. PubMed ID: 29596542, eWorksheet). This variant is reported in 1 of ~251,000 alleles in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187207/). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.