ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2873A>G (p.Glu958Gly) (rs587778069)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766496 SCV000209714 uncertain significance not provided 2021-05-24 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 29470806, 31159747, 28652578, 33875564)
Ambry Genetics RCV000159703 SCV000215022 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-12 criteria provided, single submitter clinical testing The p.E958G variant (also known as c.2873A>G), located in coding exon 18 of the ATM gene, results from an A to G substitution at nucleotide position 2873. The glutamic acid at codon 958 is replaced by glycine, 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 RCV000528438 SCV000622371 uncertain significance Ataxia-telangiectasia syndrome 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 958 of the ATM protein (p.Glu958Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs587778069, ExAC 0.07%). This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 133611). 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, but 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.
Color Health, Inc RCV000159703 SCV000682085 likely benign Hereditary cancer-predisposing syndrome 2020-02-04 criteria provided, single submitter clinical testing
GeneKor MSA RCV000159703 SCV000821842 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000528438 SCV001653365 uncertain significance Ataxia-telangiectasia syndrome 2021-05-18 criteria provided, single submitter clinical testing
ITMI RCV000120128 SCV000084266 not provided not specified 2013-09-19 no assertion provided reference population
Natera, Inc. RCV000528438 SCV001461097 uncertain significance Ataxia-telangiectasia syndrome 2020-01-04 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355117 SCV001549906 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Glu958Gly variant was identified in 2 of 2020 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer and was present in 1 of 4362 control chromosomes (frequency: 0.0002) from healthy individuals (Bodian 2014, Singh 2017). The variant was also identified in dbSNP (ID: rs587778069) as "With Uncertain Significance allele" and in the ClinVar (5x as Uncertain significance by Invitae, Ambry Genetics, GeneDx and two other submitters) database. The variant was not identified in LOVD 3.0 database. It was identified in control databases in 24 of 246208 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33580 chromosomes (freq: 0.00003), European in 1 of 111676 chromosomes (freq: 0.000009), and South Asian in 22 of 30780 chromosomes (freq: 0.0007), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian or Finnish populations. The p.Glu958 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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