ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5644C>T (p.Arg1882Ter) (rs786204433)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169043 SCV000220201 likely pathogenic Ataxia-telangiectasia syndrome 2014-03-27 criteria provided, single submitter literature only
Invitae RCV000169043 SCV000261294 pathogenic Ataxia-telangiectasia syndrome 2020-09-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1882 (p.Arg1882*) of 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 in both the compound heterozygous and homozygous form (PMID: 12552559, 15039971, 23322442, 12815592, 21665257) and in individuals with breast cancer (PMID: 25625042). ClinVar contains an entry for this variant (Variation ID: 188737). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000213135 SCV000277013 pathogenic Hereditary cancer-predisposing syndrome 2019-02-18 criteria provided, single submitter clinical testing The p.R1882* pathogenic mutation (also known as c.5644C>T), located in coding exon 36 of the ATM gene, results from a C to T substitution at nucleotide position 5644. This changes the amino acid from an arginine to a stop codon within coding exon 36. This mutation has been previously reported in multiple homozygous and compound heterozygous individuals with ataxia telangiectasia (Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31; Jeddane L et al. Neuromolecular Med. 2013 Jun;15:288-94). It has also been identified in a series of 100 sporadic breast cancer patients from Brazil (Mangone FR et al. Springerplus. 2015 Jan;4:23), as well as in a cohort of 323 Spanish hereditary breast cancer patients (Graña B et al. Breast Cancer Res. Treat. 2011 Jul;128:573-9). 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 RCV000235346 SCV000293155 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.5644C>T at the cDNA level and p.Arg1882Ter (R1882X) 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 has been reported in the homozygous or compound heterozygous state in several individuals with ataxia telangiectasia (Buzin 2002, Mitui 2003, Jeddane 2013), and in the heterozygous state in individuals with breast cancer (Decker 2017, Renault 2018). We consider this variant to be pathogenic.
Color Health, Inc RCV000213135 SCV000687632 pathogenic Hereditary cancer-predisposing syndrome 2020-11-10 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 37 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 both in the homozygous state and in the compound heterozygous state with a second ATM mutation individuals affected with ataxia-telangiectasia (PMID: 12552559, 12815592, 15039971, 21665257, 23322442). This variant has not been identified 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000235346 SCV001249809 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing

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