ClinVar Miner

Submissions for variant NM_001351834.2(ATM):c.1402_1403del (p.Lys468fs) (rs587781347)

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Total submissions: 6
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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 Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl RCV000169588 SCV000221096 likely pathogenic Ataxia-telangiectasia syndrome 2015-01-28 criteria provided, single submitter literature only
Invitae RCV000169588 SCV000260603 pathogenic Ataxia-telangiectasia syndrome 2019-12-18 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 observed in individuals affected with breast cancer (PMID: 24733792, 26094658), as well as in the homozygous or compound heterozygous state in individuals with ataxia-telangiectasia (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.
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.
Color RCV000129125 SCV000681977 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169588 SCV001426959 pathogenic Ataxia-telangiectasia syndrome 2020-07-03 criteria provided, single submitter clinical testing Variant summary: ATM c.1402_1403delAA (p.Lys468GlufsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant allele was found at a frequency of 4e-05 in 251414 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.1402_1403delAA has been reported in the literature in homozygous and compound heterozygous genotypes among multiple individuals affected with Ataxia-Telangiectasia (example, Broeks_1998, Lin_2010, Buzin_2003, Carney_2012, Jeddane_2013), and in heterozygosity among multiple individuals with a variety of cancers, such as breast and ovarian (example, Kurian_2015, Alorafi_2015, Manchana_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Carney_2012). The most pronounced variant effect results in a complete absence of ATM protein as measured by western blot and no ATM activity. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

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