Submissions for variant NM_000051.4(ATM):c.6100C>T (p.Arg2034Ter)

dbSNP: rs532480170

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235108	SCV000149131	pathogenic	not provided	2023-04-04	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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26270727, 8659541, 12552559, 11505391, 28724667, 30612635, 29922827, 35047863, 25525159, 14695186, 15390180, 10330348, 21833744, 0, 27913932, 26681312, 26845104, 29731985, 29478780, 29555771, 28767289, 30322717, 30607632, 31980526, 31948886, 35886069, 35729272, 35260754, 34308104)
Invitae	RCV000122867	SCV000166125	pathogenic	Ataxia-telangiectasia syndrome	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2034*) 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 (rs532480170, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia, breast cancer and multiple cancer types (PMID: 8659541, 11505391, 21833744, 26681312, 26845104). ClinVar contains an entry for this variant (Variation ID: 127417). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000115222	SCV000214025	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	The p.R2034* pathogenic mutation (also known as c.6100C>T), located in coding exon 41 of the ATM gene, results from a C to T substitution at nucleotide position 6100. This changes the amino acid from an arginine to a stop codon within coding exon 41. This alteration has been reported in multiple individuals with ataxia telangiectasia (Telatar M et al. Am. J. Hum. Genet. 1996 Jul;59(1):40-4; Soukupova J et al. Neuromolecular Med. 2011 Sep;13(3):204-11). It was also described breast and colon cancer cohorts (Angele S et al. Hum. Mutat. 2003 Feb;21(2):169-70; AlDubayan SH et al. Am. J. Hum. Genet. 2018 03;102(3):401-414). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000115222	SCV000266019	likely pathogenic	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115222	SCV000292138	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 42 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 reported in the homozygous state and compound heterozygous state in individuals affected with ataxia telangiectasia (PMID: 8659541, 21833744, 25122203, 34954471). This variant has also been reported in individuals affected with breast, endometrial, thyroid, pancreatic, gastric, and kidney cancer (PMID: 11505391, 14695186, 19781682, 26681312, 28767289, 30607632, 32963463). This variant has been identified in 2/282742 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.
Baylor Genetics	RCV000122867	SCV000807216	pathogenic	Ataxia-telangiectasia syndrome	2017-09-01	criteria provided, single submitter	clinical testing	This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a missense mutation in a 10-year-old male with global delays, myopathy, epilepsy, generalize muscle weakness, and abnormal brain MRI.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122867	SCV001442640	pathogenic	Ataxia-telangiectasia syndrome	2020-10-19	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6100C>T (p.Arg2034X) 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 251344 control chromosomes (gnomAD). c.6100C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (e.g. Telatar_1996, Buzin_2003, Soukupova_2011, An_2016) and was also reported in heterozygous state in patients affected by various tumor phenotypes (e.g. Shindo_2017, Yang_2019). These data indicate that the variant is very likely to be associated with disease. 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000235108	SCV001446661	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000235108	SCV002010797	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000122867	SCV002021940	pathogenic	Ataxia-telangiectasia syndrome	2019-04-17	criteria provided, single submitter	clinical testing
3billion	RCV000122867	SCV002521496	pathogenic	Ataxia-telangiectasia syndrome	2022-05-22	criteria provided, single submitter	clinical testing	This variant has been reported as pathogenic more than twice (ClinVar ID: VCV000127417, PMID:8659541), along with assertion criteria based on the ACMG guidelines. It has been reported with an extremely low frequency in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset. The substitution creates a nonsense variant, which is expected to cause a loss of normal protein function via nonsense-mediated mRNA decay. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV001762221	SCV002581591	pathogenic	Familial cancer of breast	2022-07-13	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235108	SCV002760728	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001762221	SCV003936016	pathogenic	Familial cancer of breast	2023-06-06	criteria provided, single submitter	clinical testing	A known pathogenic mutation in the ATM gene (c.6100C>T). This sequence change creates a premature translational stop signal (p.Arg2034*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with ataxia-telangiectasia, breast cancer and multiple cancer types (PMID: 8659541, 21833744, 11505391, 26845104, 26681312). ClinVar contains an entry for this variant (Variation ID: 127417) with 9 submissions, all of which describe it as pathogenic/likely pathogenic, two stars, no conflicts. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). In-silico predictions show pathogenic computational verdict based on 4 pathogenic predictions from BayesDel_addAF, DANN, FATHMM-MKL and MutationTaster vs 1 benign prediction from EIGEN. Therefore, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001762221	SCV004209421	pathogenic	Familial cancer of breast	2023-09-20	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000235108	SCV004229272	pathogenic	not provided	2023-05-09	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with ataxia-telangiectasia, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Myriad Genetics, Inc.	RCV001762221	SCV004933506	pathogenic	Familial cancer of breast	2024-01-29	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.
Natera, Inc.	RCV000122867	SCV001457404	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing