ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.103C>T (p.Arg35Ter) (rs55861249)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130278 SCV000185123 pathogenic Hereditary cancer-predisposing syndrome 2017-06-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification
Color RCV000130278 SCV000681949 pathogenic Hereditary cancer-predisposing syndrome 2017-02-21 criteria provided, single submitter clinical testing
Counsyl RCV000003164 SCV000485098 pathogenic Ataxia-telangiectasia syndrome 2016-07-18 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
Fulgent Genetics RCV000515417 SCV000611163 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-18 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.
GeneReviews RCV000003164 SCV000328289 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Genetic Services Laboratory, University of Chicago RCV000003164 SCV000246611 pathogenic Ataxia-telangiectasia syndrome 2014-06-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000003164 SCV000826949 pathogenic Ataxia-telangiectasia syndrome 2018-06-14 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. Truncating variants in ATM are known to be pathogenic. This particular truncation 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). 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 ). 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
OMIM RCV000003164 SCV000023322 pathogenic Ataxia-telangiectasia syndrome 1996-12-01 no assertion criteria provided literature only
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

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