ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4921G>C (p.Asp1641His) (rs587782896)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132535 SCV000187632 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000132535 SCV000687584 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing
Counsyl RCV000225809 SCV000791168 uncertain significance Ataxia-telangiectasia syndrome 2017-05-01 criteria provided, single submitter clinical testing
GeneDx RCV000478375 SCV000570645 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.4921G>C at the cDNA level, p.Asp1641His (D1641H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant has been observed in both normal and tumor tissue samples from individuals with lung adenocarcinoma (Lu 2015, Lai 2016). ATM Asp1641His was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Aspartic Acid and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Asp1641His occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Asp1641His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000225809 SCV000282972 uncertain significance Ataxia-telangiectasia syndrome 2019-01-11 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 1641 of the ATM protein (p.Asp1641His). 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 (rs587782896, ExAC 0.002%). This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 143016). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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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