ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1339C>T (p.Arg447Ter) (rs587779815)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115141 SCV000172928 pathogenic Hereditary cancer-predisposing syndrome 2018-05-10 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)
Color RCV000115141 SCV000537674 pathogenic Hereditary cancer-predisposing syndrome 2016-04-19 criteria provided, single submitter clinical testing
Counsyl RCV000169409 SCV000220813 likely pathogenic Ataxia-telangiectasia syndrome 2014-10-17 criteria provided, single submitter literature only
GeneDx RCV000211960 SCV000149050 pathogenic not provided 2018-08-10 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.1339C>T at the cDNA level and p.Arg447Ter (R447X) at the protein level. The substitution creates a nonsense variant, changing an Arginine to a premature stop codon (CGA>TGA). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the homozygous or compound heterozygous state in individuals with ataxia-telangiectasia (Gilad 1996, Fares 2004, Perez-Villena 2013, Hoche 2014, Kraus 2014). ATM Arg447Ter has also been observed in an individual with prostate cancer (Pritchard 2016). We consider this variant to be pathogenic.
GenomeConnect, ClinGen RCV000211960 SCV000607155 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Integrated Genetics/Laboratory Corporation of America RCV000169409 SCV000694179 pathogenic Ataxia-telangiectasia syndrome 2016-12-05 criteria provided, single submitter clinical testing Variant summary: The ATM c.1339C>T (p.Arg447X) 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.3049C>T/p.Gln1017X, c.4396C>T/p.Arg1466X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121264 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant has been reported as germline variant in mutliple Ataxia-Telangiectasia patients in autosomal recessive inheritance and patients with ovarian cancer, chronic lymphocyti leukemia or prostate cancer in autosomal dominant inheritance. It also has been reported in at least one patient with aggressive cutaneous squamous cell carcinoma as a somatic variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000169409 SCV000622246 pathogenic Ataxia-telangiectasia syndrome 2018-11-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg447*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587779815, ExAC 0.01%). This variant has been reported in several individuals affected with ataxia-telangiectasia (PMID: 8845835, 15164409, 23612382, 24789685), and individuals affected with ovarian and prostate cancer (PMID: 26681312, 27433846). ClinVar contains an entry for this variant (Variation ID: 127337). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.

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