ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1271C>A (p.Pro424His) (rs147472613)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164384 SCV000215019 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000164384 SCV000292200 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
GeneDx RCV000218574 SCV000278810 uncertain significance not provided 2018-05-03 criteria provided, single submitter clinical testing This variant is denoted ATM c.1271C>A at the cDNA level, p.Pro424His (P424H) at the protein level, and results in the change of a Proline to a Histidine (CCT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Pro424His was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Pro424His is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Pro424His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000526201 SCV000622245 uncertain significance Ataxia-telangiectasia syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 424 of the ATM protein (p.Pro424His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases (rs147472613, ExAC 0.01%). This variant has been observed in an individual with breast cancer (PMID: 30086788). ClinVar contains an entry for this variant (Variation ID: 185031). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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