ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.4087A>G (p.Thr1363Ala)

dbSNP: rs587779837
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115186 SCV000149095 uncertain significance not provided 2014-01-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.4087A>G at the cDNA level, p.Thr1363Ala (T1363A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr1363Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative substitution in which a neutral polar amino acid is replaced with a neutral non-polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on the currently available information, we consider ATM Thr1363Ala to be a variant of uncertain significance.
Ambry Genetics RCV000574275 SCV000667928 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-08 criteria provided, single submitter clinical testing The p.T1363A variant (also known as c.4087A>G), located in coding exon 26 of the ATM gene, results from an A to G substitution at nucleotide position 4087. The threonine at codon 1363 is replaced by alanine, an amino acid with similar properties. This alteration was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet Med, 2015 Aug;17:630-8). This amino acid position is 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000628153 SCV000749046 uncertain significance Ataxia-telangiectasia syndrome 2022-09-27 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1363 of the ATM protein (p.Thr1363Ala). This variant is present in population databases (rs587779837, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 127381). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Color Diagnostics, LLC DBA Color Health RCV000574275 SCV000904609 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-21 criteria provided, single submitter clinical testing

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