ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.496+4T>C (rs587781375)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129193 SCV000183932 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585055 SCV000692729 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing
Color RCV000129193 SCV000902853 likely benign Hereditary cancer-predisposing syndrome 2016-05-18 criteria provided, single submitter clinical testing
Counsyl RCV000474202 SCV000799740 uncertain significance Ataxia-telangiectasia syndrome 2018-05-03 criteria provided, single submitter clinical testing
GeneDx RCV000211949 SCV000209584 benign not specified 2014-06-23 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.
Integrated Genetics/Laboratory Corporation of America RCV000211949 SCV000916580 uncertain significance not specified 2018-06-04 criteria provided, single submitter clinical testing Variant summary: ATM c.496+4T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.9e-05 in 277060 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer or AT, allowing no conclusion about variant significance. c.496+4T>C has been reported in the literature in individuals affected with Breast Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with disease. At-least one case of a co-occurrence with a possible pathogenic variant in the STK11 gene has been reported (c.375-1C>T, STK11, Jalkh_2017) providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000474202 SCV000546724 uncertain significance Ataxia-telangiectasia syndrome 2018-12-15 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs587781375, ExAC 0.02%). This variant has been observed in individuals affected with a personal and/or family history of breast cancer (PMID: 28202063). ClinVar contains an entry for this variant (Variation ID: 140926). 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 is not likely to affect RNA splicing, 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.
Mendelics RCV000474202 SCV000838471 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000129193 SCV000787868 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-21 no assertion criteria provided clinical testing

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