ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1A>G (p.Met1Val) (rs730881359)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000258119 SCV000678094 likely pathogenic Ataxia-telangiectasia syndrome 2016-11-29 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001093019 SCV001249794 likely pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV001175687 SCV001339384 pathogenic Hereditary cancer-predisposing syndrome 2020-09-01 criteria provided, single submitter clinical testing This variant results in the loss of the translation start codon (methionine at codon 1) of the ATM gene. This variant is expected to disrupt the expression of the full-length ATM protein. The next in-frame methionine occurs at codon 94, but it has not been shown if a functional ATM protein product can be produced using p.Met94 as an alternative translation start site. This variant has been reported in trans with p.Gly2891Asp variant in an individual affected with breast cancer and mild ataxia-telangiectasia (PMID: 22146522). Cells derived from this patient showed 10-20% of kinase activity compared to normal cells. A functional study has shown that the cells transfected with this variant construct show a very low level expression of a truncated protein, probably due to the use of a downstream methionine for translation initiation (PMID: 22146522). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Invitae RCV000258119 SCV001583011 pathogenic Ataxia-telangiectasia syndrome 2020-03-12 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 individual(s) with ataxia-telangiectasia (PMID: 22146522, 21665257, 21792198, 9463314). ClinVar contains an entry for this variant (Variation ID: 181942). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000258119 SCV000328265 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355020 SCV001549777 pathogenic Familial pancreatic carcinoma no assertion criteria provided clinical testing The ATM c.1A>G variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs730881359) as “With Pathogenic, other” allele ,ClinVar (classified as pathogenic by GeneReviews and as likely pathogenic by Counsyl).The variant was not identified in the LOVD 3.0 database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1A>G variant occurs in the first base of the translation initiation site (the methionine amino acid start site), increasing the likelihood this variant may disrupt translation or lead to an abnormal protein product. The variant was observed in a breast cancer patient with severe reaction to radiotherapy who was found to have 2 ATM mutations: c.1A>G and c.8672G>A (Byrd, 2012). The mutations were found to be on different alleles, and the c.8762G>A allele's resulting mutant protein was expressed and shown to have some residual ATM kinase activity in lymphoblastoid and skin fibroblast cell lines. The c.1A>G variant was hypothesized to ablate the initiation of ATM protein translation entirely but the possibility of the expression of ATM protein if the GUG of the RNA were able to allow translation could not be ruled out. The possibility that initiation from a downstream methionine resulting in a truncated protein was also considered. The c.1A>G mutation was modelled individually by site-directed mutagenesis of full-length normal ATM cDNA. Very low protein levels were observed and the molecular weight was lower that wild type protein, and the kinase level or the resulting protein was too low to be measured in this assay. These observations were consistent with a second patient with a different mutation of the initiation codon. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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