ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.2818A>G (p.Lys940Glu)

gnomAD frequency: 0.00001  dbSNP: rs1064795896
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479895 SCV000572128 uncertain significance not provided 2017-12-11 criteria provided, single submitter clinical testing This variant is denoted ATM c.2818A>G at the cDNA level, p.Lys940Glu (K940E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Lys940Glu was not observed in large population cohorts (Lek 2016). Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Lys940Glu is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Lys940Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000549701 SCV000622364 uncertain significance Ataxia-telangiectasia syndrome 2023-12-31 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 940 of the ATM protein (p.Lys940Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30426508). ClinVar contains an entry for this variant (Variation ID: 422618). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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 RCV000771385 SCV000903711 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-14 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamic acid at codon 940 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 an individual affected with bilateral breast cancer; however, this individual also carried a pathogenic variant in PALB2 (PMID: 30426508). This variant has not been identified 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.
Ambry Genetics RCV000771385 SCV002749488 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-12 criteria provided, single submitter clinical testing The p.K940E variant (also known as c.2818A>G), located in coding exon 17 of the ATM gene, results from an A to G substitution at nucleotide position 2818. The lysine at codon 940 is replaced by glutamic acid, an amino acid with similar properties. This alteration was identified in a patient with bilateral breast cancer at 48; however, this patient was also found to carry a pathogenic alteration in the PALB2 gene (Schubert S et al. Int J Cancer, 2019 06;144:2683-2694). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV004568200 SCV005057015 uncertain significance Familial cancer of breast 2024-02-06 criteria provided, single submitter clinical testing

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