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 2019-02-04 criteria provided, single submitter clinical testing The p.N619H variant (also known as c.1855A>C), located in coding exon 11 of the ATM gene, results from an A to C substitution at nucleotide position 1855. The asparagine at codon 619 is replaced by histidine, an amino acid with similar properties. This amino acid position is well conserved through mammals. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000203692 SCV000260170 uncertain significance Ataxia-telangiectasia syndrome 2020-10-18 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.
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001530924 SCV000694201 uncertain significance not specified 2021-06-28 criteria provided, single submitter clinical testing Variant summary: ATM c.1855A>C (p.Asn619His) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250960 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1855A>C has been previously reported in one uterine serous carcinoma sample without confirmation of its origin (germline vs somatic) (Jones_2015) and a CLL patient (Tiao_2017). These reports do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc RCV000131223 SCV000902882 likely benign Hereditary cancer-predisposing syndrome 2016-06-29 criteria provided, single submitter clinical testing

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