ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1261T>C (p.Ser421Pro) (rs376196220)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165683 SCV000216421 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000203884 SCV000260461 uncertain significance Ataxia-telangiectasia syndrome 2018-09-03 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 421 of the ATM protein (p.Ser421Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 186145). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000480887 SCV000570634 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing This variant is denoted ATM c.1261T>C at the cDNA level, p.Ser421Pro (S421P) at the protein level, and results in the change of a Serine to a Proline (TCA>CCA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Ser421Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Ser421Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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