ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.748C>T (p.Arg250Ter) (rs772821016)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196975 SCV000253745 pathogenic Ataxia-telangiectasia syndrome 2019-12-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg250*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs772821016, ExAC 0.009%). This variant has been observed in the compound heterozygous state in several individuals affected with ataxia-telangiectasia (PMID: 10330348, 12552559, 22006793), and as heterozygous in an individual with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 216024). Experimental studies have shown that this change results in exon 7 skipping (reported as exon 9 in the literature) (PMID: 22006793, 10330348). 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 RCV000216766 SCV000275923 pathogenic Hereditary cancer-predisposing syndrome 2018-03-27 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl RCV000196975 SCV000486919 pathogenic Ataxia-telangiectasia syndrome 2016-09-07 criteria provided, single submitter clinical testing
GeneDx RCV000479464 SCV000566881 pathogenic not provided 2018-12-10 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.748C>T at the cDNA level and p.Arg250Ter (R250X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA). In addition, ATM Arg250Ter has also been shown to result in skipping of exon 9 (Teraoka 1999, Nakamura 2012). Both the nonsense and aberrant splicing alterations are predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual with breast cancer and in the compound heterozygous state in at least four individuals with ataxia-telangiectasia (Teraoka 1999, Buzin 2002, Broccoletti 2011, Nakamura 2012, Sun 2017). Based on currently available evidence, we consider this variant to be pathogenic.
Mendelics RCV000196975 SCV000838476 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000216766 SCV000904432 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Academic Department of Medical Genetics, University of Cambridge RCV000216766 SCV000992200 pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.

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