ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.4510A>G (p.Thr1504Ala)

gnomAD frequency: 0.00001  dbSNP: rs767466937
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001022614 SCV001184369 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-08 criteria provided, single submitter clinical testing The p.T1504A variant (also known as c.4510A>G), located in coding exon 29 of the ATM gene, results from an A to G substitution at nucleotide position 4510. The threonine at codon 1504 is replaced by alanine, an amino acid with similar properties. 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.
Invitae RCV001041858 SCV001205504 uncertain significance Ataxia-telangiectasia syndrome 2022-09-07 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 1504 of the ATM protein (p.Thr1504Ala). This variant is present in population databases (rs767466937, gnomAD 0.02%). 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: 824962). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. 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 RCV001759710 SCV001996825 uncertain significance not provided 2019-11-05 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV001041858 SCV002526053 uncertain significance Ataxia-telangiectasia syndrome 2022-05-04 criteria provided, single submitter clinical testing The ATM c.4510A>G (p.Thr1504Ala) missense change has a maximum subpopulation frequency of 0.015% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant (BP4), but to our knowledge functional assays have not been performed. To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia or hereditary breast cancer. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria, as specified by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel: BP4.
Color Diagnostics, LLC DBA Color Health RCV001022614 SCV004360985 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-05 criteria provided, single submitter clinical testing This missense variant replaces threonine with alanine at codon 1504 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has been identified in 3/282714 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Natera, Inc. RCV001041858 SCV001462330 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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