ClinVar Miner

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

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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 RCV000223021 SCV000276125 pathogenic Hereditary cancer-predisposing syndrome 2017-08-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other ACMG-defined mutation (i.e. initiation codon or gross deletion)
Color RCV000223021 SCV000682174 pathogenic Hereditary cancer-predisposing syndrome 2016-12-15 criteria provided, single submitter clinical testing
Counsyl RCV000169261 SCV000220551 likely pathogenic Ataxia-telangiectasia syndrome 2014-07-25 criteria provided, single submitter literature only
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.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000169261 SCV000547133 pathogenic Ataxia-telangiectasia syndrome 2018-12-14 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.

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