ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6114C>G (p.His2038Gln) (rs774993357)

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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 RCV000219254 SCV000276456 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-10 criteria provided, single submitter clinical testing
Color RCV000219254 SCV000903698 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-24 criteria provided, single submitter clinical testing
GeneDx RCV000482636 SCV000572203 uncertain significance not provided 2017-12-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.6114C>G at the cDNA level, p.His2038Gln (H2038Q) at the protein level, and results in the change of a Histidine to a Glutamine (CAC>CAG). This variant was identified in a cohort of 1250 individuals with personal history of Lynch syndrome-associated cancer and/or polyps undergoing genetic testing for Lynch syndrome using a multi-gene panel (Yurgelun 2015). ATM His2038Gln was not observed in large population cohorts (Lek 2016). ATM His2038Gln is located in the FAT domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM His2038Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000628144 SCV000749037 uncertain significance Ataxia-telangiectasia syndrome 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 2038 of the ATM protein (p.His2038Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual who was reported to have a personal history of Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 232340). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, 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.

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