ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3G>A (p.Met1Ile) (rs781404312)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169261 SCV000220551 likely pathogenic Ataxia-telangiectasia syndrome 2014-07-25 criteria provided, single submitter literature only
Ambry Genetics RCV000223021 SCV000276125 pathogenic Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing The p.M1? pathogenic mutation (also known as c.3G>A), located in coding exon 1 of the ATM gene, results from an G to A substitution at nucleotide position 3. This alters the methionine amino acid at the initiation codon. This mutation has been detected in conjunction with a second ATM mutation in two patients with ataxia telangiectasia (Buzin CH, Hum. Mutat. 2003 Feb; 21(2):123-31). It was also identified in 2/13087 breast cancer cases and 0/5488 control individuals in the UK as well as a familial pancreatic cancer kindred in the US (Decker B et al. J. Med. Genet., 2017 Nov;54:732-741; Shindo K et al. J. Clin. Oncol., 2017 Oct;35:3382-3390). In addition to the clinical data presented in the literature, 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. <br />
GeneDx RCV000215466 SCV000278806 pathogenic not provided 2017-08-24 criteria provided, single submitter clinical testing The c.3G>A variant in the ATM gene alters the initiator Methionine codon, and the resultant protein would be described as “p.Met1?” to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. This variant has been reported in the compound heterozygous state with other pathogenic ATM variants in two individuals with Ataxia-telangiectasia (Buzin 2003) and is considered pathogenic.
Invitae RCV000169261 SCV000547133 pathogenic Ataxia-telangiectasia syndrome 2020-10-26 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the ATM mRNA. The next in-frame methionine is located in exon 4 (p.Met94). This variant is present in population databases (rs781404312, ExAC 0.01%). This variant has been reported to co-occur with other pathogenic ATM variants in two unrelated individuals affected with ataxia-telangiectasia (PMID: 12552559). ClinVar contains an entry for this variant (Variation ID: 188901). A different nucleotide change affecting the same initiator codon (c.2T>C) has been previously classified as pathogenic (Invitae), based on strong functional data suggesting that the use of an alternate downstream ATG leads to the expression of a smaller, truncated ATM protein with no kinase activity (PMID: 22146522, 21593342, 21792198) and genetic evidence in several patients with ataxia-telangiectasia (PMID: 8845835, 12552559, 22649200, 9463314, 21792198). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000223021 SCV000682174 pathogenic Hereditary cancer-predisposing syndrome 2020-07-28 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ataxia-telangiectasia, breast cancer, and pancreatic cancer (PMID: 12552559, 28767289, 28779002). This variant has been identified in 1/251388 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169261 SCV000694270 likely pathogenic Ataxia-telangiectasia syndrome 2016-11-04 criteria provided, single submitter clinical testing Variant summary: The ATM c.3G>A (p.Met1Ile) variant involves the alteration of the initiation codon and would be expected to prevent all protein translation or an abnormal protein using an alternate Methionine codon. There are no published functional studies for the variant. This variant was found in 1/121348 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant has been reported in two A-T patients in compound heterozygous state with another deleterious variant (Buzin_2003). Multiple clinical diagnostic laboratories have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is currently classified as Likely Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000215466 SCV001448151 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000215466 SCV001879453 pathogenic not provided 2021-01-20 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity ( This variant is expected to interfere with initiation of protein synthesis. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including both ataxia-telangiectasia (A-T) and cancer patients (PMID: 12552559, 28779002, 28767289, 31285527).

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