ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6975G>C (p.Ala2325=) (rs556778314)

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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 RCV000215860 SCV000277317 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000215860 SCV000682381 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764940 SCV000896112 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000481810 SCV000564655 uncertain significance not provided 2018-01-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.6975G>C at the DNA level. It is silent at the coding level, preserving an Alanine at codon 2325. In-silico analyses, which include splice predictors and evolutionary conservation, are uninformative in their assessment as to whether or not the variant is damaging. This variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism. However, this variant has been reported as a somatic variant in a Ewing sarcoma cell line (Crompton 2014). ATM c.6975G>C was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether ATM c.6975G>C is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000538344 SCV000622705 uncertain significance Ataxia-telangiectasia syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change affects codon 2325 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. This variant also falls at the last nucleotide of exon 47 of the ATM coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 233023). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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.
True Health Diagnostics RCV000215860 SCV000787880 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-22 no assertion criteria provided clinical testing

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