ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1402_1403del (p.Lys468fs) (rs587781347)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129125 SCV000183842 pathogenic Hereditary cancer-predisposing syndrome 2012-11-19 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 RCV000129125 SCV000681977 pathogenic Hereditary cancer-predisposing syndrome 2016-12-05 criteria provided, single submitter clinical testing
Counsyl RCV000169588 SCV000221096 likely pathogenic Ataxia-telangiectasia syndrome 2015-01-28 criteria provided, single submitter literature only
GeneDx RCV000236583 SCV000292779 pathogenic not provided 2019-01-04 criteria provided, single submitter clinical testing This deletion of two nucleotides in ATM is denoted c.1402_1403delAA at the cDNA level and p.Lys468GlufsX18 (K468EfsX18) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGAC[delAA]GAGG. The deletion causes a frameshift, which changes a Lysine to a Glutamic Acid at codon 468, and creates a premature stop codon at position 18 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.1402_1403delAA, previously reported as 1403delAA or 1787delAA, has been observed in individuals with breast cancer (Kurian 2014, Aloraifi 2015) and in the homozygous or compound heterozygous state in several families with Ataxia-telangiectasia (Broeks 1998, Buzin 2003, Carney 2012, Jeddane 2013, Huang 2013, Chen 2013). We consider this variant to be pathogenic.
Invitae RCV000169588 SCV000260603 pathogenic Ataxia-telangiectasia syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys468Glufs*18) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587781347, ExAC 0.03%). This variant has been reported in individuals affected with breast cancer (PMID: 24733792, 26094658), as well as in the homozygous or compound heterozygous state in individuals with ataxia-telangiectasia (A-T) (PMID: 9792409, 12552559, 23322442, 22649200, 20308662). ClinVar contains an entry for this variant (Variation ID: 140889). 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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