ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4279G>A (p.Ala1427Thr) (rs2229021)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130581 SCV000185453 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-24 criteria provided, single submitter clinical testing The p.A1427T variant (also known as c.4279G>A), located in coding exon 28 of the ATM gene, results from a G to A substitution at nucleotide position 4279. The alanine at codon 1427 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This amino acid position is not well conserved in available vertebrate species. 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.
GeneDx RCV000222514 SCV000278825 uncertain significance not provided 2021-05-18 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Hirsch 2008, Tavtigian 2009); This variant is associated with the following publications: (PMID: 17333338, 19781682, 22529920, 30197789)
Invitae RCV000467455 SCV000546875 uncertain significance Ataxia-telangiectasia syndrome 2020-09-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1427 of the ATM protein (p.Ala1427Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs2229021, ExAC 0.02%). This variant has been reported in individuals affected with breast cancer (PMID: 17333338, 19781682). ClinVar contains an entry for this variant (Variation ID: 141884). 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 threonine 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.
Counsyl RCV000467455 SCV000792232 uncertain significance Ataxia-telangiectasia syndrome 2017-06-13 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000222514 SCV000859746 uncertain significance not provided 2018-03-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130581 SCV000911024 likely benign Hereditary cancer-predisposing syndrome 2016-06-21 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV001257474 SCV001434280 uncertain significance Familial cancer of breast 2019-10-29 criteria provided, single submitter clinical testing This variant has been reported in the literature in individuals with breast cancer (Hirsch 2008, Tavtigian 2009). This variant has an overall allele frequency of 0.00003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4
Nilou-Genome Lab RCV000467455 SCV001653347 uncertain significance Ataxia-telangiectasia syndrome 2021-05-18 criteria provided, single submitter clinical testing

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