ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5890A>G (p.Lys1964Glu) (rs201963507)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130965 SCV000185880 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000130965 SCV000537568 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515322 SCV000611368 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000212034 SCV000209753 uncertain significance not specified 2017-09-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.5890A>G at the cDNA level, p.Lys1964Glu (K1964E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). ATM Lys1964Glu has been observed in at least two individuals with breast and/or ovarian cancer, and was absent from unaffected controls (Thorstenson 2003, Tavtigian 2009, Goldgar 2011). This variant was also reported in an individual undergoing multigene cancer panel testing due to a history of a Lynch syndrome-related cancer and/or polyps (Yurgelun 2015). ATM Lys1964Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Lys1964Glu occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in the FAT domain (Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Lys1964Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000130965 SCV000821862 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000585940 SCV000694309 uncertain significance not provided 2016-12-09 criteria provided, single submitter clinical testing Variant summary: The c.5890A>G (p.Lys1964Glu) in ATM gene is a missense change that involves a conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant of interest is located within the FAT domain, however, the functional impact of this missense change is yet to be studied. The variant is present in the large control population dataset of ExAC at a frequency 0.0001 (13 /121054chrs tested), which does not exceed the estimated maximal expected allele frequency of a pathogenic variant in this gene (0.001). The variant has been reported in affected individuals presented with BrC, LS or CLL, but without strong evidence for causality. In addition, several reputable databases/clinical laboratories cite the variant as VUS. At this time there is no sufficient evidence to classify this variant with confidence. Taken together, the variant was classified as VUS until more data becomes available.
Invitae RCV000197688 SCV000254126 likely benign Ataxia-telangiectasia syndrome 2017-12-26 criteria provided, single submitter clinical testing
Mendelics RCV000197688 SCV000838561 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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