ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7390T>C (p.Cys2464Arg) (rs55801750)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000202803 SCV000149158 likely benign not specified 2017-10-26 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000119204 SCV000153946 benign Ataxia-telangiectasia syndrome 2019-12-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115249 SCV000186389 benign Hereditary cancer-predisposing syndrome 2015-11-12 criteria provided, single submitter clinical testing No disease association in appropriately sized case-control study(ies);Intact protein function observed in appropriate functional assay(s);In silico models in agreement (benign)
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000202803 SCV000257606 uncertain significance not specified 2015-07-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000202803 SCV000694351 benign not specified 2019-02-22 criteria provided, single submitter clinical testing Variant summary: ATM c.7390T>C (p.Cys2464Arg) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 282084 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00042 vs 0.001). However, this variant has been reported in 16/9884 (0.0016) women older than age 70 and cancer free. This frequency is higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0016 vs 0.001), suggesting this variant does not associate with cancer. c.7390T>C has been reported in the literature in individuals affected with Breast Cancer. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported in our internal database (CHEK2 c.1100delC, p.Thr367fsX15; TP53 c.782+1G>T), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (1x Benign, 2 x Likely benign, 4x VUS). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000119204 SCV000743734 uncertain significance Ataxia-telangiectasia syndrome 2016-10-06 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000119204 SCV000745131 uncertain significance Ataxia-telangiectasia syndrome 2016-02-25 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589438 SCV000780404 uncertain significance not provided 2018-01-01 criteria provided, single submitter clinical testing
Color RCV000115249 SCV000910578 benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
Mendelics RCV000119204 SCV001138562 uncertain significance Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000119204 SCV001261060 uncertain significance Ataxia-telangiectasia syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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