ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.4466G>A (p.Arg1489His)

gnomAD frequency: 0.00004  dbSNP: rs201594549
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159726 SCV000209738 uncertain significance not provided 2023-04-24 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer and prostate cancer (Decker et al., 2017; Girard et al., 2019; Karlsson et al., 2021); This variant is associated with the following publications: (PMID: 28779002, 30287823, 30303537, 33436325, 32980694, 27535533)
Ambry Genetics RCV000217727 SCV000276493 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-04 criteria provided, single submitter clinical testing The p.R1489H variant (also known as c.4466G>A), located in coding exon 29 of the ATM gene, results from a G to A substitution at nucleotide position 4466. The arginine at codon 1489 is replaced by histidine, an amino acid with highly similar properties. 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 RCV000467957 SCV000547038 uncertain significance Ataxia-telangiectasia syndrome 2022-11-03 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1489 of the ATM protein (p.Arg1489His). This variant is present in population databases (rs201594549, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 30303537). ClinVar contains an entry for this variant (Variation ID: 181959). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Color Diagnostics, LLC DBA Color Health RCV000217727 SCV000687551 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-17 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 1489 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 been reported in individuals affected with breast cancer and in one or more unaffected control individual in breast cancer case-control studies (PMID: 28779002, 30287823). This variant has been identified in 4/282602 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.
Athena Diagnostics RCV000159726 SCV000840941 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV003467232 SCV004210070 uncertain significance Familial cancer of breast 2024-02-21 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003467232 SCV005084005 likely benign Familial cancer of breast 2024-05-20 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Natera, Inc. RCV000467957 SCV002084748 uncertain significance Ataxia-telangiectasia syndrome 2020-12-04 no assertion criteria provided clinical testing

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