ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4420C>G (p.His1474Asp) (rs587779840)

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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 RCV000115196 SCV000214609 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115196 SCV000903206 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-07 criteria provided, single submitter clinical testing
GeneDx RCV000212016 SCV000149105 uncertain significance not provided 2018-06-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.4420C>G at the cDNA level, p.His1474Asp (H1474D) at the protein level, and results in the change of a Histidine to an Aspartic Acid (CAC>GAC). This variant was observed in an individual undergoing multigene cancer panel testing due to a history of breast cancer (Tung 2016). ATM His1474Asp 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 a deleterious effect. Based on currently available evidence, it is unclear whether ATM His1474Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000206587 SCV000259589 uncertain significance Ataxia-telangiectasia syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 1474 of the ATM protein (p.His1474Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 127391). 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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