ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2449G>C (p.Asp817His) (rs587778067)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656758 SCV000209703 uncertain significance not provided 2018-10-29 criteria provided, single submitter clinical testing This variant is denoted ATM c.2449G>C at the cDNA level, p.Asp817His (D817H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant was observed in 1/381 individuals with endometrial cancer undergoing multi-gene panel testing and at least one Latino woman with breast cancer (Tung 2015, Ring 2016). ATM Asp817His was also identified in 1/118 healthy Hispanic individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. ATM Asp817His was observed at an allele frequency of 0.2% (66/33,570) in individuals of Latino ancestry 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 Asp817His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159695 SCV000218248 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000168026 SCV000218678 uncertain significance Ataxia-telangiectasia syndrome 2019-12-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 817 of the ATM protein (p.Asp817His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs587778067, ExAC 0.2%). This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 133608). 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.
Color RCV000159695 SCV000292218 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-19 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV001250428 SCV001424789 uncertain significance Familial cancer of breast 2019-09-10 criteria provided, single submitter clinical testing This variant has been reported in the literature in an individual with endometrial cancer and an individual with breast cancer (Tung 2015, Ring 2016). This variant has a combined allele frequency of 0.0003 in the Broad Institute gnomAD Browser ( and is more common in individuals of Latinx ancestry (Lek 2016). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk.
ITMI RCV000120124 SCV000084262 not provided not specified 2013-09-19 no assertion provided reference population

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