ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3993G>C (p.Gln1331His) (rs863224566)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206293 SCV000262350 uncertain significance Ataxia-telangiectasia syndrome 2015-11-06 criteria provided, single submitter clinical testing This sequence change affects a highly conserved nucleotide near the donor splice site. It also falls at the last nucleotide of exon 26 of the ATM mRNA. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature. This missense change is not expected to affect splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a novel missense change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000221742 SCV000273958 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon
GeneDx RCV000479019 SCV000569334 uncertain significance not provided 2017-06-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.3993G>C at the cDNA level, p.Gln1331His (Q1331H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAC). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in colorectal and lung cancer (Peifer 2012, Betge 2015, Ma 2017). ATM Gln1331His was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Gln1331His occurs at a position that is conserved across species and is not located in a known functional domain. While protein-based in silico analyses predict that this variant is probably damaging to protein structure and function, multiple splicing models predict that this variant may damage or weaken the nearby natural splice donor site and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether ATM Gln1331His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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