ClinVar Miner

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

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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 RCV000166918 SCV000217737 pathogenic Hereditary cancer-predisposing syndrome 2018-08-20 criteria provided, single submitter clinical testing The p.M1? pathogenic mutation (also known as c.1A>C), located in coding exon 1 of the ATM gene, results from an A to C substitution at nucleotide position 1. This alters the methionine amino acid at the initiation codon. While this exact alteration has not been previously described in the literature, two other disease-causing mutations at the initiation codon, c.3G>A and c.2T>C, have been reported in a compound heterozygous state in patients with Ataxia Telengectasia (AT) (Gilad S, Hum. Mol. Genet. 1996 Apr; 5(4):433-9. Buzin CH, Hum. Mutat. 2003 Feb; 21(2):123-31). Another alteration at the initiation codon, c.1A>G, has been identified in trans with an additional ATM alteration in a patient with very mild AT symptoms. Functional analysis of the two alterations independently revealed that the c.1A>G allele produced very low protein levels, and the protein that was produced was of a lower molecular weight than wild type ATM suggesting initiation at a downstream methionine resulting in a premature truncation codon (Byrd PJ, Br. J. Cancer 2012 Jan; 106(2):262-8). Since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation.
Counsyl RCV000576648 SCV000678178 likely pathogenic Ataxia-telangiectasia syndrome 2017-01-20 criteria provided, single submitter clinical testing
Baylor Genetics 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 2020-06-29 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.
Color Health, Inc RCV000166918 SCV001339383 pathogenic Hereditary cancer-predisposing syndrome 2020-09-01 criteria provided, single submitter clinical testing This variant results in the loss of translation initiation methionine codon 1 of the ATM protein. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in trans with a pathogenic missense mutation in a child affected with hypotonia, ataxic gait, short stature, dysmorphic features (Clinvar variation ID: 187213 and SCV000807215.1) and in an individual affected with early-onset breast cancer (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different translation initiation codon loss variant (ATM c.2T>C / p.Met1?) is a well documented pathogenic variant (Clinvar variation ID: 187213). Based on the available evidence, this variant is classified as Pathogenic.

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