ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6154G>A (p.Glu2052Lys) (rs202206540)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000159743 SCV000216022 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Deficient protein function in appropriate functional assay(s)
Color RCV000159743 SCV000911078 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-06 criteria provided, single submitter clinical testing
GeneDx RCV000212039 SCV000209758 likely pathogenic not provided 2018-10-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.6154G>A at the cDNA level, p.Glu2052Lys (E2052K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant was observed in the homozygous state in an individual with ataxia telangiectasia, and cDNA derived from this patient was identified to have ATM transcripts with exon 42 deleted, also known as exon 44 using alternate nomenclature, and absence of ATM protein by Western blot (Teraoka 1999). Although ATM Glu2052Lys is not predicted to affect splicing by published and internal splicing models, authors suggest that this variant may alter the secondary structure of the transcript, which may disrupt the formation of the spliceosome (Teraoka 1999). This variant was also identified in trans with an ATM frameshift variant in multiple members of a family affected with cervical dopa-responsive dystonia, elevated AFP, and telangiectasias (Charlesworth 2013), as well as in an individual with bilateral breast cancer and a family history of pancreatic cancer (Kraus 2017). ATM Glu2052Lys was observed at an allele frequency of 0.03% (5/16476) in individuals of South Asian ancestry in large population cohorts (Lek 2016). ATM Glu2052Lys is located in the FAT domain (Stracker 2013). Based on the currently available evidence, we consider ATM Glu2052Lys to be a likely pathogenic variant.
GeneReviews RCV000167963 SCV000328267 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Invitae RCV000167963 SCV000218611 uncertain significance Ataxia-telangiectasia syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2052 of the ATM protein (p.Glu2052Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs202206540, ExAC 0.03%). This variant has been reported to segregate in one family with dopa-responsive dystonia in individuals who also carry a loss-of-function variant (c.7886_7890del) on the opposite chromosome (in trans) in the ATM gene. One family member who presented with typical manifestations of ataxia-telangiectasia (A-T) was homozygous for the c.7886_7890del variant and did not carry the p.Glu2052Lys variant (PMID: 23946315). This variant was also found to be homozygous in an individual with A-T, and heterozygous in several individuals with breast cancer (PMID: 10330348, 27616075, 29470806). However, it has also been observed in trans with a pathogenic variant in ATM in an individual not affected with A-T, indicating that this variant might not be causative of disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 181975). An experimental study using a lymphoblastoid cell line derived from an A-T affected individual has shown that this missense change can produce a defect in RNA splicing and loss of ATM protein (PMID: 10330348). 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.

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