ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3981A>T (p.Leu1327Phe) (rs1064794874)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482123 SCV000570128 uncertain significance not provided 2016-05-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.3981A>T at the cDNA level, p.Leu1327Phe (L1327F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTA>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu1327Phe 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 Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. ATM Leu1327Phe occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Leu1327Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568454 SCV000665505 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000684962 SCV000812427 uncertain significance Ataxia-telangiectasia syndrome 2018-01-31 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1327 of the ATM protein (p.Leu1327Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 421049). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Fulgent Genetics,Fulgent Genetics RCV000763701 SCV000894581 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing

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