ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1A>C (p.Met1Leu) (rs730881359)

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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 RCV000166918 SCV000217737 pathogenic Hereditary cancer-predisposing syndrome 2014-11-25 criteria provided, single submitter clinical testing
Baylor Miraca Genetics Laboratories, RCV000576648 SCV000807215 pathogenic Ataxia-telangiectasia syndrome 2017-09-01 criteria provided, single submitter clinical testing This start codon mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory in trans with a pathogenic missense mutation in a 3-year-old male with hypotonia, ataxic gait, short stature, dysmorphic features.
Counsyl RCV000576648 SCV000678178 likely pathogenic Ataxia-telangiectasia syndrome 2017-01-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000576648 SCV000918503 likely pathogenic Ataxia-telangiectasia syndrome 2017-10-20 criteria provided, single submitter clinical testing Variant summary: The ATM c.1A>C (p.Met1Leu) variant involves the alteration of a conserved nucleotide causing a substitution of initiation codon in exon 2 and is located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) (InterPro). 2/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Since this variant affects the initiation codon, it is expected to alter the translation of ATM protein. Two other substitution variants in the initiation codon (p.Met1Ile and p.Met1Thr) have been classified as likely pathogenic/pathogenic by our laboratory. This variant is absent in 215414 control chromosomes in gnomAD. One clinical diagnostic laboratory has classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Invitae RCV000576648 SCV000941428 pathogenic Ataxia-telangiectasia syndrome 2018-11-12 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the ATM mRNA. The next in-frame methionine is located at codon 94. This variant is not present in population databases (ExAC no frequency). Disruption of the initiator codon has been observed in several individuals affected with ataxia-telangiectasia (PMID: 9463314, 12552559, 21792198, 22649200). ClinVar contains an entry for this variant (Variation ID: 187213). For these reasons, this variant has been classified as Pathogenic.

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