ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4776+2T>C (rs587781927)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130284 SCV000185129 pathogenic Hereditary cancer-predisposing syndrome 2016-11-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000235350 SCV000293433 pathogenic not provided 2016-11-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.4776+2T>C or IVS31+2T>C and consists of a T>C nucleotide substitution at the +2 position of intron 31 of the ATM gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing. This variant, also known as IVS33+2T>C, has been reported in the homozygous and compound heterozygous state in individuals with Ataxia-telangiectasia (Gilad 1998, Mitui 2003). Functional studies showed a cell line with this variant in the homozygous state exhibited radiosensitivity consistent with classic Ataxia-telangiectasia cell lines (Curry 1989, Gilad 1998). We therefore consider this variant to be pathogenic.
Counsyl RCV000003170 SCV000794146 pathogenic Ataxia-telangiectasia syndrome 2017-09-15 criteria provided, single submitter clinical testing
Invitae RCV000003170 SCV000836117 pathogenic Ataxia-telangiectasia syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 31 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in the homozygous state in twin sisters affected with ataxia-telangiectasia and on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with ataxia-telangiectasia (PMID: 9497252, 12815592). These findings are consistent with autosomal recessive inheritance, and suggest that this variant contributes to disease. This variant is also known as IVS33+2T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 141672). Experimental studies have shown that this sequence change results in skipping of exon 31 of the ATM mRNA. Exon 31 is also known as exon 32 in the literature. Fibroblasts derived from a homozygous patient showed increased radiosensitivity in in vitro assays (PMID: 9497252, 2491181). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000003170 SCV000838546 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000003170 SCV000918553 pathogenic Ataxia-telangiectasia syndrome 2018-07-24 criteria provided, single submitter clinical testing Variant summary: ATM c.4776+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 244642 control chromosomes. c.4776+2T>C has been reported in the literature in at least two individuals affected with Ataxia-Telangiectasia, one of whom is homozygous for the variant with classic A-T with microcephaly and intellectual disability (Gilad_1998). These data indicate that the variant may be associated with disease. Gilad et al. also report experimental evidence suggesting a loss of ATM protein product in the patient's fibroblast cell line, though the data was not presented for review. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Furthermore, c.4776+2T>A has also been reported to associate with Ataxia-Telangiectasia. Based on the evidence outlined above, the variant was classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000003170 SCV000996056 pathogenic Ataxia-telangiectasia syndrome 2017-02-17 criteria provided, single submitter clinical testing The c.4776+2T>C canonical splice donor site variant is predicted to cause abnormal gene splicing. This variant, also known as IVS33+2T>C, has been previously reported in the homozygous and compound heterozygous state in individuals with Ataxia-Telangiectasia (AT) (PMID: 9711876). Functional studies showed that this variant led to in-frame skipping of exon 30, previously referred to as exon 32, and a cell line with this variant in the homozygous state exhibited radiosensitivity (PMID: 9497252, 2491181). Based on the combined evidence, this variant is classified as pathogenic.
OMIM RCV000003170 SCV000023328 pathogenic Ataxia-telangiectasia syndrome 1998-03-01 no assertion criteria provided literature only

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