ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.103C>T (p.Arg35Ter) (rs55861249)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 16
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130278 SCV000185123 pathogenic Hereditary cancer-predisposing syndrome 2018-07-22 criteria provided, single submitter clinical testing The p.R35* pathogenic mutation (also known as c.103C>T), located in coding exon 2 of the ATM gene, results from a C to T substitution at nucleotide position 103. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been previously reported in a homozygous state in multiple individuals of North African Jewish ancestry with ataxia-telangiectasia (A-T). Additionally, the allele frequency in North African Jewish individuals with A-T has been reported at 97%, as compared to 29% in the healthy North African Jewish population, strongly indicating a founder effect in this population (Gilad S et al. Hum. Mol. Genet. 1996 Dec;5:2033-7). The p.R35* mutation was subsequently identified in both Hispanic and Sephardic Jewish A-T families sharing the same SNP haplotype, suggesting that this mutation has spread to other ethnicities over time as a result of migration (Campbell C et al. Hum. Mutat. 2003 Jan;21:80-5). Furthermore, functional studies show that this mutation leads to the elimination of ATM protein synthesis (Gilad S et al. Hum. Mol. Genet. 1996 Dec;5:2033-7) as well as increased radiosensitivity (Gutiérrez-Enríquez S et al. Genes Chromosomes Cancer. 2004 Jun;40:109-19) in lymphoblastoid cell lines homozygous for this mutation. 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.
Genetic Services Laboratory, University of Chicago RCV000003164 SCV000246611 pathogenic Ataxia-telangiectasia syndrome 2014-06-27 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000130278 SCV000266013 likely pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000236608 SCV000293091 pathogenic not provided 2018-02-19 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.103C>T at the cDNA level and p.Arg35Ter (R35X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant was observed in 32/33 defective ATM alleles in Jewish A-T families of North African origin (Gilad 1996). In addition, the mutation was shown to be functionally abnormal, inducing aberrant splicing (Xiong 2014) and exhibiting defects in a cell line after exposure to ionizing radiation (Gutiérrez-Enríquez 2004). It is considered pathogenic.
Counsyl RCV000003164 SCV000485098 pathogenic Ataxia-telangiectasia syndrome 2016-07-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515417 SCV000611163 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130278 SCV000681949 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Invitae RCV000003164 SCV000826949 pathogenic Ataxia-telangiectasia syndrome 2020-10-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 35 (p.Arg35*). It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs55861249, ExAC 0.009%). This variant has been reported as a common variant in individuals of North African Jewish descent affected with ataxia telangiectasia (A-T) (PMID: 8968760), as well as in individuals of other ethnicities affected with A-T (PMID: 21665257) and in an individual affected with breast cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 3025). Experimental studies using A-T patients' cells that are homozygous for this variant have shown that they are more sensitive to radiation-induced damage compared to normal cells (PMID: 15101044, 17699107), a result consistent with an absent or truncated ATM protein (PMID: 8968760, 12637545 ). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000003164 SCV000838465 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000236608 SCV000854897 pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000003164 SCV000916531 pathogenic Ataxia-telangiectasia syndrome 2018-05-09 criteria provided, single submitter clinical testing Variant summary: Variant summary: The ATM c.103C>T (p.Arg35X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.513C>G, p.Tyr171X; c.790delT, p.Tyr264fsX12; c.1027_1030delGAAA, p.Glu343fsX2). One in silico tool predicts a damaging outcome for this variant. This variant was found in 8/246618 control chromosomes at a frequency of 0.0000324, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). The variant was reported in numerous affected individuals in the literature, and is known as a North African Jewish founder mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000236608 SCV001447901 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000236608 SCV001502086 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
OMIM RCV000003164 SCV000023322 pathogenic Ataxia-telangiectasia syndrome 1996-12-01 no assertion criteria provided literature only
GeneReviews RCV000003164 SCV000328289 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Natera, Inc. RCV000003164 SCV001461804 pathogenic Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.