ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.2838G>T (p.Met946Ile)

dbSNP: rs1317505466
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001238542 SCV001411360 uncertain significance Ataxia-telangiectasia syndrome 2023-10-27 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 946 of the ATM protein (p.Met946Ile). This variant also falls at the last nucleotide of exon 18, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 28486781). ClinVar contains an entry for this variant (Variation ID: 964345). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Breakthrough Genomics, Breakthrough Genomics RCV001238542 SCV005088832 likely pathogenic Ataxia-telangiectasia syndrome 2020-06-28 criteria provided, single submitter clinical testing This variant lies in the essential splice donor site of exon 18 of the ATM gene and alters a conserved residue in the protein. In-silico splice prediction tool (NNSPLICE) suggests that this variant might affect splicing due to the loss of constitutive splice site and introduction of a new splice site, which in turn might lead to a frameshift and consequent premature termination of the protein; this will likely result in loss-of-function. The variant seems to be a novel variant, as it has not been previously reported in population or public databases or in the literature.

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