ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1855A>C (p.Asn619His) (rs140882609)

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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 RCV000131223 SCV000186175 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000131223 SCV000902882 likely benign Hereditary cancer-predisposing syndrome 2016-06-29 criteria provided, single submitter clinical testing
GeneDx RCV000587634 SCV000278811 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing This variant is denoted ATM c.1855A>C at the cDNA level, p.Asn619His (N619H) at the protein level, and results in the change of an Asparagine to a Histidine (AAC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Asn619His was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Asparagine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Asn619His 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 information, it is unclear whether ATM Asn619His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587634 SCV000694201 uncertain significance not provided 2017-03-03 criteria provided, single submitter clinical testing Variant summary: The ATM c.1855A>C (p.Asn619His) variant involves the alteration of a conserved nucleotide and is predicted to be benign by 3/4 in silico tools (SNPs&GO not captured due to low reliability index). The variant is located outside of known functional domains in ATM protein (InterPro, UniProt). This variant was found in 2/118178 control chromosomes from ExAC at a frequency of 0.0000169, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). It has been previously reported in one uterine serous carcinoma sample without confirmation of its origin (germline vs somatic) and without evidence for or against pathogenicity (Jones_2015). Multiple clinical diagnostic laboratories have classified this variant as "uncertain significance". Based on the currently available information, this variant is classified as Variant of Unknown Significance (VUS).
Invitae RCV000203692 SCV000260170 uncertain significance Ataxia-telangiectasia syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 619 of the ATM protein (p.Asn619His). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs140882609, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 142224). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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